Post on 25-Jun-2020
5152017
1
Mycology in the FutureArturo Casadevall
Johns Hopkins Bloomberg School of Public Health
ON PREDICTION
Its tough making predictions especially about the futureldquoYogi Berra
1899 FIN DE SIECLE FUNGAL DISEASES EXTREMELY RARE
TUBERCULOSIS
DIPHTHERIA
POLIO
ANTHRAX PLAGUE
VARIOLAMEASLES MALARIA
TRYPANOSOMESHELMINTHS
TYPHUS
SYPHILIS
1999 FIN DE SIECLE FUNGAL DISEASES DISTRESSINGLY COMMON
Candida albicansCryptococcus neoformans
Coccidioides immitis Aspergillus spp
WHAT HAPPENEDHOSTS CHANGED
5152017
2
THE HOST WAS ALTERED
MEDICAL PROGRESS
A CATACLYSM
ANTIBIOTICS IMMUNOSUPPRESANTSCHEMOTHERAPY ICUrsquos
Park et al AIDS 2009
106 DEATHSY
IV Lines
MYCOLOGICAL FUTURISM VISIONS
bull NEW FUNGAL DISEASES
bull EMBRACING THE X AXIS
bull ENHANCING THE SYMBIONT
bull A RENEWED FOCUS ON THE HOST
bull CONTINUED INCREASING IMPORTANCE
NEW FUNGAL DISEASES
PEOPLE FEAR VIRAL BACTERIAL AND PARASITIC DISEASES
BUT NOT FUNGAL DISEASES WHY
FUNGI ARE DEVASTING ECOSYSTEMS
Corals Frogs Rice
Salamanders Turtles Wheat
Puccinia graminis
Gorgonia ventalina B dendrobatidis
B salmandrivorans Fusarium solani
Magnaporte oryzae
Snakes
O ophiodiicola
5152017
3
ADAPTIVE IMMUNITY AND TEMPERATURE ARE SYNERGISTIC IMPORTANT (JOHN PERFECT AND OTHERS)
+SYSTEMICINFECTION
TESTICULARINFECTION
T = 40-41 C
HEALTHYRABBITTHAT CLEARSINFECTION
STEROIDS
CHRONICORCHITIS
C neoformans
EMERGING PATTERN
ADAPTIVE IMMUNITY + ENDOTHERMY = RESISTANCE
TO FUNGAL DISEASES
BAT WHITE NOSE SYNDROME
RAISING TEMPERATURE CAN CURE FUNGAL DISEASES
bull BATS CAN BE CURED OF WHITE NOSE SYNDROME BY PROVIDING THEM WITH FOOD WHICH ALLOWS THEM TO RAISE THEIR TEMPERATURES
bull FROGS ARE CURED OF CHYTRID BY PLACING THEM ON A 37oC WARM ROOM
bull FOR INSECTS AND ECTOTHERMIC VERTEBRATES INDUCED FEVERS (BEHAVIOR SUN) INCREASES SURVIVAL
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
TEMPERATURE TOLERANCES FOR FUNGI
Robert amp Casadevall JID 2009
TOLERANCE IS DEFINED AS THE ABILITY TO GROW
THERMAL TOLERANCE DECLINES RAPIDLY IN THE 30-40 oC RANGE
MOST FUNGAL SPECIES DO NOT POSE A THREAT TOHUMANS BECAUSE OF THERMAL INTOLERANCE
Vincent Robert
5152017
4
CONSIDERING FITNESS AS A FUNCTION OF TEMPERATURE PREDICTS MAXIMAL FITNESS AT
MAMMALIAN TEMPERATURES
BASAL TEMPERATURE (K)
FITNESS
mBIO 2010
367 C
The metabolic rate scales with body mass as
B micro M3
4
Reaction kinetics vary with temperature
according to Boltzmannrsquos factor as
e-Ei
kT
The metabolic rate is proportional to the
product of these two effects and have been
shown to be well approximated in biologically
relevant temperature range (0C -40C) as
B(T) micro M3
4e-Ei
kT
THE COSTThe benefit is calculated as the reduction in fungi
species capable of infecting a host
Found to be approximately by s=6 for every
degree Celsius in the temperature range 27C-40C
THE BENEFIT
F(T) micro F0[1- (1- s)T ]
HYPOTHESIS A FUNGAL FILTER SELECTED FOR MAMMALS OVER REPTILES
AGE OF REPTILES
AGE OF MAMMALS
Science 2001
GLOBAL COMPOST
ENDOTHERM SELECTION
AGE OF MAMMALS
SCIENCE 2003
FUNGALSELECTIONCREATES A
FILTER FOR THEEMERGENCE OF MAMMALS
REPTILIAN MEGAFAUNA MAMMALIAN MEGAFAUNA
Courtesy of NIAID
GEOGRAPHIC FACTS MOST ENDEMIC MYCOSES OCCUR IN TROPICAL AND SUB-TROPICAL REGIONS
DISTRIBUTION amp PHYLOGENY OF THERMAL TOLERANCE IN FUNGI (BMC BIOLOGY 2015)
FUNGAL THERMAL TOLERANCE
bull NOT MONOPHYLETIC
bull ASCO gt BASIDIO
bull CORRELATED WITH LATITUDE
bull CORRELATED WITH CAPACITY FOR FERMENTATION
Ascomycetes Basidiomycetes
HIGH AND LOW TOLERANCESDISCONTINOUS - DIFFERENT
MECHANISMS
THERMAL TOLERANCECORRELATED WITH ABILITYTO FERMENT SOME SUGARS
5152017
5
AVERAGE FUNGAL THERMAL TOLERANCES OVER PAST 30 YEARS
Robert et al BMC Biology (2015)
ALT-VIRULENCE HYPOTHESIS
bull Posits that the capacity for microbial virulence emerges by alternative selection forces independent of the final host
bull These selection forces involve both abiotic (temperature humidity etc) and biotic (amoeba etc) causes
bull Views the emergence of virulence as a continuous stochastic process
bull For fungal pathogens there is now considerable evidence that grazing by amoeboid predators selects for traits that confer upon the microbe the capacity for mammalian virulence
Kamilla Xavier Gomes
Grad Student
A CASTELLANI PHAGOCYTOSIS KINETICS WITH SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
Allan GuimaraesPrincipal
Investigator at theFluminense
Federal University
PATHOGENIC FUNGI DISPLAY HIGHER VIRULENCE IN GALLERIA MELLONELA AFTER GROWTH IN THE PRESENCE OF A CASTELLANI
UNPUBLISHED Gomes K X In Preparation
5152017
6
A CASTELLANII SURFACE EXTRACT LABELS THE SURFACE OF SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
AMOEBA AND OTHER FUNGI
M anisopliaeB bassiana
Paracoccidioides brasiliensis
ILDINETE SILVA RIVERAPATRICIA ALBQUERQUELABORATORIES
Environ Microbiol Rep 2013 Dec5(6)819-24Interaction of Aspergillus fumigatus conidia with Acanthamoeba castellanii parallels macrophage-fungus interactionsVan Waeyenberghe L1 Bareacute J Pasmans F ClaeysM Bert W Haesebrouck F Houf K Martel A
SO WHY ARE SOME MICROBES PATHOGENIC AND OTHERS NOT (PROVIDED THERE IS A SUSCEPTIBLE HOST)
CASADEVALL MICROBE (2006)
AMOEBAE WORMS HEAT
SELECTIVE PRESSURES
ENVIROMENTAL MICROBES POSSESSTRAITS THA CAN FUNCTION IN VIRULENCE
THE CARDS OF VIRULENCE
MICROBIAL CARD lsquoHANDSrsquoONLY SOME lsquoHANDSrsquo CONFER PATHOGENIC POTENTIAL
MAMMALIANlsquoHANDrsquo
INSECTlsquoHANDrsquo
PLANTlsquoHANDrsquo
lsquoMARTIANHANDrsquo
lsquoNON-PATHOGENICrsquo
Microbe 2006
5152017
7
SOME PREDICTIONShellip
bull NEW FUNGAL DISEASES WILL APPEAR
bull FIRST EMERGENCE IN WARMER CLIMATES
bull FIRST EVIDENCE MAY COME IN COOLER MAMMALS
bull MORE PATHOGENIC BASIDIOMYCES
bull SOME MAY BE RESISTANT TO ALL ANTIFUNGALS
ASSESSMENT OF THREAT WOULD REQUIRE GREATER KNOWLEDGE OF FUNGAL BIOLOGY ECOLOGY THERMAL SUSCEPTIBILITY
COMPARISON OF VIRULENCE FOR THREE CRYPTOCOCCAL SPECIES
Cyptococcus podzolicus
Modified Findley K et al Eukaryotic Cell 8(3)353-361 2009
32 C39 C
34 CGALLERIA MELONELLA ALLOWS
LOWER TEMPERATURES
RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA
PHOSPHOLIPASE +UREASE +
BOTTOM LINE CONSISTENT WITH THE CONCEPT OF EMERGENCE THE PRESENCE OFVIRULENCE FACTORS WAS NOT PREDICTIVE FOR VIRULENCE
CAPSULE + CAPSULE +
MELANIN +
CAPSULE -
MELANIN -
C neoformans C amylolentus C podzolicus
EMBRACING THE X AXIS
THERE HAS BEEN LITTLE PROGRESS IN TREATING FUNGAL DISEASES IN A GENERATION WITH REGARDS TO REDUCING MORBIDITY AND MORTALITY ndash DRUGS ARE NOT ENOUGHT
5152017
8
BASIC RELATIONSHIP FOR lsquoDAMAGE-RESPONSE FRAMEWORKrsquo
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
Casadevall amp Pirofski Nature Micro Rev 2003
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
VIRULENCE IS A MICROBIAL PROPERTY THATIS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
ANTIBOTICSWORK PRIMARILY ON THE YAXIS BY REDUCINGINNOCULUM
IMMUNOMODULATION THE VIEW FROM THE DAMAGE-RESPONSE FRAMEWORK
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
ENHANCE
IMMUNITY
REDUCE
IMMUNITY
DISSEMINATED TB
ADD IFN-gTB MEINGITISADD STEROIDS
MYCOTIC DISEASES OCCUR AT BOTH HORNS OF THE PARABOLA
Aspergillus spp
DISSEMINATED
ASPERGILLOSISABPAASTHMASINUSITIS
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
2
THE HOST WAS ALTERED
MEDICAL PROGRESS
A CATACLYSM
ANTIBIOTICS IMMUNOSUPPRESANTSCHEMOTHERAPY ICUrsquos
Park et al AIDS 2009
106 DEATHSY
IV Lines
MYCOLOGICAL FUTURISM VISIONS
bull NEW FUNGAL DISEASES
bull EMBRACING THE X AXIS
bull ENHANCING THE SYMBIONT
bull A RENEWED FOCUS ON THE HOST
bull CONTINUED INCREASING IMPORTANCE
NEW FUNGAL DISEASES
PEOPLE FEAR VIRAL BACTERIAL AND PARASITIC DISEASES
BUT NOT FUNGAL DISEASES WHY
FUNGI ARE DEVASTING ECOSYSTEMS
Corals Frogs Rice
Salamanders Turtles Wheat
Puccinia graminis
Gorgonia ventalina B dendrobatidis
B salmandrivorans Fusarium solani
Magnaporte oryzae
Snakes
O ophiodiicola
5152017
3
ADAPTIVE IMMUNITY AND TEMPERATURE ARE SYNERGISTIC IMPORTANT (JOHN PERFECT AND OTHERS)
+SYSTEMICINFECTION
TESTICULARINFECTION
T = 40-41 C
HEALTHYRABBITTHAT CLEARSINFECTION
STEROIDS
CHRONICORCHITIS
C neoformans
EMERGING PATTERN
ADAPTIVE IMMUNITY + ENDOTHERMY = RESISTANCE
TO FUNGAL DISEASES
BAT WHITE NOSE SYNDROME
RAISING TEMPERATURE CAN CURE FUNGAL DISEASES
bull BATS CAN BE CURED OF WHITE NOSE SYNDROME BY PROVIDING THEM WITH FOOD WHICH ALLOWS THEM TO RAISE THEIR TEMPERATURES
bull FROGS ARE CURED OF CHYTRID BY PLACING THEM ON A 37oC WARM ROOM
bull FOR INSECTS AND ECTOTHERMIC VERTEBRATES INDUCED FEVERS (BEHAVIOR SUN) INCREASES SURVIVAL
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
TEMPERATURE TOLERANCES FOR FUNGI
Robert amp Casadevall JID 2009
TOLERANCE IS DEFINED AS THE ABILITY TO GROW
THERMAL TOLERANCE DECLINES RAPIDLY IN THE 30-40 oC RANGE
MOST FUNGAL SPECIES DO NOT POSE A THREAT TOHUMANS BECAUSE OF THERMAL INTOLERANCE
Vincent Robert
5152017
4
CONSIDERING FITNESS AS A FUNCTION OF TEMPERATURE PREDICTS MAXIMAL FITNESS AT
MAMMALIAN TEMPERATURES
BASAL TEMPERATURE (K)
FITNESS
mBIO 2010
367 C
The metabolic rate scales with body mass as
B micro M3
4
Reaction kinetics vary with temperature
according to Boltzmannrsquos factor as
e-Ei
kT
The metabolic rate is proportional to the
product of these two effects and have been
shown to be well approximated in biologically
relevant temperature range (0C -40C) as
B(T) micro M3
4e-Ei
kT
THE COSTThe benefit is calculated as the reduction in fungi
species capable of infecting a host
Found to be approximately by s=6 for every
degree Celsius in the temperature range 27C-40C
THE BENEFIT
F(T) micro F0[1- (1- s)T ]
HYPOTHESIS A FUNGAL FILTER SELECTED FOR MAMMALS OVER REPTILES
AGE OF REPTILES
AGE OF MAMMALS
Science 2001
GLOBAL COMPOST
ENDOTHERM SELECTION
AGE OF MAMMALS
SCIENCE 2003
FUNGALSELECTIONCREATES A
FILTER FOR THEEMERGENCE OF MAMMALS
REPTILIAN MEGAFAUNA MAMMALIAN MEGAFAUNA
Courtesy of NIAID
GEOGRAPHIC FACTS MOST ENDEMIC MYCOSES OCCUR IN TROPICAL AND SUB-TROPICAL REGIONS
DISTRIBUTION amp PHYLOGENY OF THERMAL TOLERANCE IN FUNGI (BMC BIOLOGY 2015)
FUNGAL THERMAL TOLERANCE
bull NOT MONOPHYLETIC
bull ASCO gt BASIDIO
bull CORRELATED WITH LATITUDE
bull CORRELATED WITH CAPACITY FOR FERMENTATION
Ascomycetes Basidiomycetes
HIGH AND LOW TOLERANCESDISCONTINOUS - DIFFERENT
MECHANISMS
THERMAL TOLERANCECORRELATED WITH ABILITYTO FERMENT SOME SUGARS
5152017
5
AVERAGE FUNGAL THERMAL TOLERANCES OVER PAST 30 YEARS
Robert et al BMC Biology (2015)
ALT-VIRULENCE HYPOTHESIS
bull Posits that the capacity for microbial virulence emerges by alternative selection forces independent of the final host
bull These selection forces involve both abiotic (temperature humidity etc) and biotic (amoeba etc) causes
bull Views the emergence of virulence as a continuous stochastic process
bull For fungal pathogens there is now considerable evidence that grazing by amoeboid predators selects for traits that confer upon the microbe the capacity for mammalian virulence
Kamilla Xavier Gomes
Grad Student
A CASTELLANI PHAGOCYTOSIS KINETICS WITH SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
Allan GuimaraesPrincipal
Investigator at theFluminense
Federal University
PATHOGENIC FUNGI DISPLAY HIGHER VIRULENCE IN GALLERIA MELLONELA AFTER GROWTH IN THE PRESENCE OF A CASTELLANI
UNPUBLISHED Gomes K X In Preparation
5152017
6
A CASTELLANII SURFACE EXTRACT LABELS THE SURFACE OF SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
AMOEBA AND OTHER FUNGI
M anisopliaeB bassiana
Paracoccidioides brasiliensis
ILDINETE SILVA RIVERAPATRICIA ALBQUERQUELABORATORIES
Environ Microbiol Rep 2013 Dec5(6)819-24Interaction of Aspergillus fumigatus conidia with Acanthamoeba castellanii parallels macrophage-fungus interactionsVan Waeyenberghe L1 Bareacute J Pasmans F ClaeysM Bert W Haesebrouck F Houf K Martel A
SO WHY ARE SOME MICROBES PATHOGENIC AND OTHERS NOT (PROVIDED THERE IS A SUSCEPTIBLE HOST)
CASADEVALL MICROBE (2006)
AMOEBAE WORMS HEAT
SELECTIVE PRESSURES
ENVIROMENTAL MICROBES POSSESSTRAITS THA CAN FUNCTION IN VIRULENCE
THE CARDS OF VIRULENCE
MICROBIAL CARD lsquoHANDSrsquoONLY SOME lsquoHANDSrsquo CONFER PATHOGENIC POTENTIAL
MAMMALIANlsquoHANDrsquo
INSECTlsquoHANDrsquo
PLANTlsquoHANDrsquo
lsquoMARTIANHANDrsquo
lsquoNON-PATHOGENICrsquo
Microbe 2006
5152017
7
SOME PREDICTIONShellip
bull NEW FUNGAL DISEASES WILL APPEAR
bull FIRST EMERGENCE IN WARMER CLIMATES
bull FIRST EVIDENCE MAY COME IN COOLER MAMMALS
bull MORE PATHOGENIC BASIDIOMYCES
bull SOME MAY BE RESISTANT TO ALL ANTIFUNGALS
ASSESSMENT OF THREAT WOULD REQUIRE GREATER KNOWLEDGE OF FUNGAL BIOLOGY ECOLOGY THERMAL SUSCEPTIBILITY
COMPARISON OF VIRULENCE FOR THREE CRYPTOCOCCAL SPECIES
Cyptococcus podzolicus
Modified Findley K et al Eukaryotic Cell 8(3)353-361 2009
32 C39 C
34 CGALLERIA MELONELLA ALLOWS
LOWER TEMPERATURES
RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA
PHOSPHOLIPASE +UREASE +
BOTTOM LINE CONSISTENT WITH THE CONCEPT OF EMERGENCE THE PRESENCE OFVIRULENCE FACTORS WAS NOT PREDICTIVE FOR VIRULENCE
CAPSULE + CAPSULE +
MELANIN +
CAPSULE -
MELANIN -
C neoformans C amylolentus C podzolicus
EMBRACING THE X AXIS
THERE HAS BEEN LITTLE PROGRESS IN TREATING FUNGAL DISEASES IN A GENERATION WITH REGARDS TO REDUCING MORBIDITY AND MORTALITY ndash DRUGS ARE NOT ENOUGHT
5152017
8
BASIC RELATIONSHIP FOR lsquoDAMAGE-RESPONSE FRAMEWORKrsquo
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
Casadevall amp Pirofski Nature Micro Rev 2003
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
VIRULENCE IS A MICROBIAL PROPERTY THATIS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
ANTIBOTICSWORK PRIMARILY ON THE YAXIS BY REDUCINGINNOCULUM
IMMUNOMODULATION THE VIEW FROM THE DAMAGE-RESPONSE FRAMEWORK
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
ENHANCE
IMMUNITY
REDUCE
IMMUNITY
DISSEMINATED TB
ADD IFN-gTB MEINGITISADD STEROIDS
MYCOTIC DISEASES OCCUR AT BOTH HORNS OF THE PARABOLA
Aspergillus spp
DISSEMINATED
ASPERGILLOSISABPAASTHMASINUSITIS
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
3
ADAPTIVE IMMUNITY AND TEMPERATURE ARE SYNERGISTIC IMPORTANT (JOHN PERFECT AND OTHERS)
+SYSTEMICINFECTION
TESTICULARINFECTION
T = 40-41 C
HEALTHYRABBITTHAT CLEARSINFECTION
STEROIDS
CHRONICORCHITIS
C neoformans
EMERGING PATTERN
ADAPTIVE IMMUNITY + ENDOTHERMY = RESISTANCE
TO FUNGAL DISEASES
BAT WHITE NOSE SYNDROME
RAISING TEMPERATURE CAN CURE FUNGAL DISEASES
bull BATS CAN BE CURED OF WHITE NOSE SYNDROME BY PROVIDING THEM WITH FOOD WHICH ALLOWS THEM TO RAISE THEIR TEMPERATURES
bull FROGS ARE CURED OF CHYTRID BY PLACING THEM ON A 37oC WARM ROOM
bull FOR INSECTS AND ECTOTHERMIC VERTEBRATES INDUCED FEVERS (BEHAVIOR SUN) INCREASES SURVIVAL
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
TEMPERATURE TOLERANCES FOR FUNGI
Robert amp Casadevall JID 2009
TOLERANCE IS DEFINED AS THE ABILITY TO GROW
THERMAL TOLERANCE DECLINES RAPIDLY IN THE 30-40 oC RANGE
MOST FUNGAL SPECIES DO NOT POSE A THREAT TOHUMANS BECAUSE OF THERMAL INTOLERANCE
Vincent Robert
5152017
4
CONSIDERING FITNESS AS A FUNCTION OF TEMPERATURE PREDICTS MAXIMAL FITNESS AT
MAMMALIAN TEMPERATURES
BASAL TEMPERATURE (K)
FITNESS
mBIO 2010
367 C
The metabolic rate scales with body mass as
B micro M3
4
Reaction kinetics vary with temperature
according to Boltzmannrsquos factor as
e-Ei
kT
The metabolic rate is proportional to the
product of these two effects and have been
shown to be well approximated in biologically
relevant temperature range (0C -40C) as
B(T) micro M3
4e-Ei
kT
THE COSTThe benefit is calculated as the reduction in fungi
species capable of infecting a host
Found to be approximately by s=6 for every
degree Celsius in the temperature range 27C-40C
THE BENEFIT
F(T) micro F0[1- (1- s)T ]
HYPOTHESIS A FUNGAL FILTER SELECTED FOR MAMMALS OVER REPTILES
AGE OF REPTILES
AGE OF MAMMALS
Science 2001
GLOBAL COMPOST
ENDOTHERM SELECTION
AGE OF MAMMALS
SCIENCE 2003
FUNGALSELECTIONCREATES A
FILTER FOR THEEMERGENCE OF MAMMALS
REPTILIAN MEGAFAUNA MAMMALIAN MEGAFAUNA
Courtesy of NIAID
GEOGRAPHIC FACTS MOST ENDEMIC MYCOSES OCCUR IN TROPICAL AND SUB-TROPICAL REGIONS
DISTRIBUTION amp PHYLOGENY OF THERMAL TOLERANCE IN FUNGI (BMC BIOLOGY 2015)
FUNGAL THERMAL TOLERANCE
bull NOT MONOPHYLETIC
bull ASCO gt BASIDIO
bull CORRELATED WITH LATITUDE
bull CORRELATED WITH CAPACITY FOR FERMENTATION
Ascomycetes Basidiomycetes
HIGH AND LOW TOLERANCESDISCONTINOUS - DIFFERENT
MECHANISMS
THERMAL TOLERANCECORRELATED WITH ABILITYTO FERMENT SOME SUGARS
5152017
5
AVERAGE FUNGAL THERMAL TOLERANCES OVER PAST 30 YEARS
Robert et al BMC Biology (2015)
ALT-VIRULENCE HYPOTHESIS
bull Posits that the capacity for microbial virulence emerges by alternative selection forces independent of the final host
bull These selection forces involve both abiotic (temperature humidity etc) and biotic (amoeba etc) causes
bull Views the emergence of virulence as a continuous stochastic process
bull For fungal pathogens there is now considerable evidence that grazing by amoeboid predators selects for traits that confer upon the microbe the capacity for mammalian virulence
Kamilla Xavier Gomes
Grad Student
A CASTELLANI PHAGOCYTOSIS KINETICS WITH SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
Allan GuimaraesPrincipal
Investigator at theFluminense
Federal University
PATHOGENIC FUNGI DISPLAY HIGHER VIRULENCE IN GALLERIA MELLONELA AFTER GROWTH IN THE PRESENCE OF A CASTELLANI
UNPUBLISHED Gomes K X In Preparation
5152017
6
A CASTELLANII SURFACE EXTRACT LABELS THE SURFACE OF SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
AMOEBA AND OTHER FUNGI
M anisopliaeB bassiana
Paracoccidioides brasiliensis
ILDINETE SILVA RIVERAPATRICIA ALBQUERQUELABORATORIES
Environ Microbiol Rep 2013 Dec5(6)819-24Interaction of Aspergillus fumigatus conidia with Acanthamoeba castellanii parallels macrophage-fungus interactionsVan Waeyenberghe L1 Bareacute J Pasmans F ClaeysM Bert W Haesebrouck F Houf K Martel A
SO WHY ARE SOME MICROBES PATHOGENIC AND OTHERS NOT (PROVIDED THERE IS A SUSCEPTIBLE HOST)
CASADEVALL MICROBE (2006)
AMOEBAE WORMS HEAT
SELECTIVE PRESSURES
ENVIROMENTAL MICROBES POSSESSTRAITS THA CAN FUNCTION IN VIRULENCE
THE CARDS OF VIRULENCE
MICROBIAL CARD lsquoHANDSrsquoONLY SOME lsquoHANDSrsquo CONFER PATHOGENIC POTENTIAL
MAMMALIANlsquoHANDrsquo
INSECTlsquoHANDrsquo
PLANTlsquoHANDrsquo
lsquoMARTIANHANDrsquo
lsquoNON-PATHOGENICrsquo
Microbe 2006
5152017
7
SOME PREDICTIONShellip
bull NEW FUNGAL DISEASES WILL APPEAR
bull FIRST EMERGENCE IN WARMER CLIMATES
bull FIRST EVIDENCE MAY COME IN COOLER MAMMALS
bull MORE PATHOGENIC BASIDIOMYCES
bull SOME MAY BE RESISTANT TO ALL ANTIFUNGALS
ASSESSMENT OF THREAT WOULD REQUIRE GREATER KNOWLEDGE OF FUNGAL BIOLOGY ECOLOGY THERMAL SUSCEPTIBILITY
COMPARISON OF VIRULENCE FOR THREE CRYPTOCOCCAL SPECIES
Cyptococcus podzolicus
Modified Findley K et al Eukaryotic Cell 8(3)353-361 2009
32 C39 C
34 CGALLERIA MELONELLA ALLOWS
LOWER TEMPERATURES
RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA
PHOSPHOLIPASE +UREASE +
BOTTOM LINE CONSISTENT WITH THE CONCEPT OF EMERGENCE THE PRESENCE OFVIRULENCE FACTORS WAS NOT PREDICTIVE FOR VIRULENCE
CAPSULE + CAPSULE +
MELANIN +
CAPSULE -
MELANIN -
C neoformans C amylolentus C podzolicus
EMBRACING THE X AXIS
THERE HAS BEEN LITTLE PROGRESS IN TREATING FUNGAL DISEASES IN A GENERATION WITH REGARDS TO REDUCING MORBIDITY AND MORTALITY ndash DRUGS ARE NOT ENOUGHT
5152017
8
BASIC RELATIONSHIP FOR lsquoDAMAGE-RESPONSE FRAMEWORKrsquo
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
Casadevall amp Pirofski Nature Micro Rev 2003
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
VIRULENCE IS A MICROBIAL PROPERTY THATIS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
ANTIBOTICSWORK PRIMARILY ON THE YAXIS BY REDUCINGINNOCULUM
IMMUNOMODULATION THE VIEW FROM THE DAMAGE-RESPONSE FRAMEWORK
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
ENHANCE
IMMUNITY
REDUCE
IMMUNITY
DISSEMINATED TB
ADD IFN-gTB MEINGITISADD STEROIDS
MYCOTIC DISEASES OCCUR AT BOTH HORNS OF THE PARABOLA
Aspergillus spp
DISSEMINATED
ASPERGILLOSISABPAASTHMASINUSITIS
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
4
CONSIDERING FITNESS AS A FUNCTION OF TEMPERATURE PREDICTS MAXIMAL FITNESS AT
MAMMALIAN TEMPERATURES
BASAL TEMPERATURE (K)
FITNESS
mBIO 2010
367 C
The metabolic rate scales with body mass as
B micro M3
4
Reaction kinetics vary with temperature
according to Boltzmannrsquos factor as
e-Ei
kT
The metabolic rate is proportional to the
product of these two effects and have been
shown to be well approximated in biologically
relevant temperature range (0C -40C) as
B(T) micro M3
4e-Ei
kT
THE COSTThe benefit is calculated as the reduction in fungi
species capable of infecting a host
Found to be approximately by s=6 for every
degree Celsius in the temperature range 27C-40C
THE BENEFIT
F(T) micro F0[1- (1- s)T ]
HYPOTHESIS A FUNGAL FILTER SELECTED FOR MAMMALS OVER REPTILES
AGE OF REPTILES
AGE OF MAMMALS
Science 2001
GLOBAL COMPOST
ENDOTHERM SELECTION
AGE OF MAMMALS
SCIENCE 2003
FUNGALSELECTIONCREATES A
FILTER FOR THEEMERGENCE OF MAMMALS
REPTILIAN MEGAFAUNA MAMMALIAN MEGAFAUNA
Courtesy of NIAID
GEOGRAPHIC FACTS MOST ENDEMIC MYCOSES OCCUR IN TROPICAL AND SUB-TROPICAL REGIONS
DISTRIBUTION amp PHYLOGENY OF THERMAL TOLERANCE IN FUNGI (BMC BIOLOGY 2015)
FUNGAL THERMAL TOLERANCE
bull NOT MONOPHYLETIC
bull ASCO gt BASIDIO
bull CORRELATED WITH LATITUDE
bull CORRELATED WITH CAPACITY FOR FERMENTATION
Ascomycetes Basidiomycetes
HIGH AND LOW TOLERANCESDISCONTINOUS - DIFFERENT
MECHANISMS
THERMAL TOLERANCECORRELATED WITH ABILITYTO FERMENT SOME SUGARS
5152017
5
AVERAGE FUNGAL THERMAL TOLERANCES OVER PAST 30 YEARS
Robert et al BMC Biology (2015)
ALT-VIRULENCE HYPOTHESIS
bull Posits that the capacity for microbial virulence emerges by alternative selection forces independent of the final host
bull These selection forces involve both abiotic (temperature humidity etc) and biotic (amoeba etc) causes
bull Views the emergence of virulence as a continuous stochastic process
bull For fungal pathogens there is now considerable evidence that grazing by amoeboid predators selects for traits that confer upon the microbe the capacity for mammalian virulence
Kamilla Xavier Gomes
Grad Student
A CASTELLANI PHAGOCYTOSIS KINETICS WITH SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
Allan GuimaraesPrincipal
Investigator at theFluminense
Federal University
PATHOGENIC FUNGI DISPLAY HIGHER VIRULENCE IN GALLERIA MELLONELA AFTER GROWTH IN THE PRESENCE OF A CASTELLANI
UNPUBLISHED Gomes K X In Preparation
5152017
6
A CASTELLANII SURFACE EXTRACT LABELS THE SURFACE OF SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
AMOEBA AND OTHER FUNGI
M anisopliaeB bassiana
Paracoccidioides brasiliensis
ILDINETE SILVA RIVERAPATRICIA ALBQUERQUELABORATORIES
Environ Microbiol Rep 2013 Dec5(6)819-24Interaction of Aspergillus fumigatus conidia with Acanthamoeba castellanii parallels macrophage-fungus interactionsVan Waeyenberghe L1 Bareacute J Pasmans F ClaeysM Bert W Haesebrouck F Houf K Martel A
SO WHY ARE SOME MICROBES PATHOGENIC AND OTHERS NOT (PROVIDED THERE IS A SUSCEPTIBLE HOST)
CASADEVALL MICROBE (2006)
AMOEBAE WORMS HEAT
SELECTIVE PRESSURES
ENVIROMENTAL MICROBES POSSESSTRAITS THA CAN FUNCTION IN VIRULENCE
THE CARDS OF VIRULENCE
MICROBIAL CARD lsquoHANDSrsquoONLY SOME lsquoHANDSrsquo CONFER PATHOGENIC POTENTIAL
MAMMALIANlsquoHANDrsquo
INSECTlsquoHANDrsquo
PLANTlsquoHANDrsquo
lsquoMARTIANHANDrsquo
lsquoNON-PATHOGENICrsquo
Microbe 2006
5152017
7
SOME PREDICTIONShellip
bull NEW FUNGAL DISEASES WILL APPEAR
bull FIRST EMERGENCE IN WARMER CLIMATES
bull FIRST EVIDENCE MAY COME IN COOLER MAMMALS
bull MORE PATHOGENIC BASIDIOMYCES
bull SOME MAY BE RESISTANT TO ALL ANTIFUNGALS
ASSESSMENT OF THREAT WOULD REQUIRE GREATER KNOWLEDGE OF FUNGAL BIOLOGY ECOLOGY THERMAL SUSCEPTIBILITY
COMPARISON OF VIRULENCE FOR THREE CRYPTOCOCCAL SPECIES
Cyptococcus podzolicus
Modified Findley K et al Eukaryotic Cell 8(3)353-361 2009
32 C39 C
34 CGALLERIA MELONELLA ALLOWS
LOWER TEMPERATURES
RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA
PHOSPHOLIPASE +UREASE +
BOTTOM LINE CONSISTENT WITH THE CONCEPT OF EMERGENCE THE PRESENCE OFVIRULENCE FACTORS WAS NOT PREDICTIVE FOR VIRULENCE
CAPSULE + CAPSULE +
MELANIN +
CAPSULE -
MELANIN -
C neoformans C amylolentus C podzolicus
EMBRACING THE X AXIS
THERE HAS BEEN LITTLE PROGRESS IN TREATING FUNGAL DISEASES IN A GENERATION WITH REGARDS TO REDUCING MORBIDITY AND MORTALITY ndash DRUGS ARE NOT ENOUGHT
5152017
8
BASIC RELATIONSHIP FOR lsquoDAMAGE-RESPONSE FRAMEWORKrsquo
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
Casadevall amp Pirofski Nature Micro Rev 2003
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
VIRULENCE IS A MICROBIAL PROPERTY THATIS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
ANTIBOTICSWORK PRIMARILY ON THE YAXIS BY REDUCINGINNOCULUM
IMMUNOMODULATION THE VIEW FROM THE DAMAGE-RESPONSE FRAMEWORK
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
ENHANCE
IMMUNITY
REDUCE
IMMUNITY
DISSEMINATED TB
ADD IFN-gTB MEINGITISADD STEROIDS
MYCOTIC DISEASES OCCUR AT BOTH HORNS OF THE PARABOLA
Aspergillus spp
DISSEMINATED
ASPERGILLOSISABPAASTHMASINUSITIS
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
5
AVERAGE FUNGAL THERMAL TOLERANCES OVER PAST 30 YEARS
Robert et al BMC Biology (2015)
ALT-VIRULENCE HYPOTHESIS
bull Posits that the capacity for microbial virulence emerges by alternative selection forces independent of the final host
bull These selection forces involve both abiotic (temperature humidity etc) and biotic (amoeba etc) causes
bull Views the emergence of virulence as a continuous stochastic process
bull For fungal pathogens there is now considerable evidence that grazing by amoeboid predators selects for traits that confer upon the microbe the capacity for mammalian virulence
Kamilla Xavier Gomes
Grad Student
A CASTELLANI PHAGOCYTOSIS KINETICS WITH SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
Allan GuimaraesPrincipal
Investigator at theFluminense
Federal University
PATHOGENIC FUNGI DISPLAY HIGHER VIRULENCE IN GALLERIA MELLONELA AFTER GROWTH IN THE PRESENCE OF A CASTELLANI
UNPUBLISHED Gomes K X In Preparation
5152017
6
A CASTELLANII SURFACE EXTRACT LABELS THE SURFACE OF SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
AMOEBA AND OTHER FUNGI
M anisopliaeB bassiana
Paracoccidioides brasiliensis
ILDINETE SILVA RIVERAPATRICIA ALBQUERQUELABORATORIES
Environ Microbiol Rep 2013 Dec5(6)819-24Interaction of Aspergillus fumigatus conidia with Acanthamoeba castellanii parallels macrophage-fungus interactionsVan Waeyenberghe L1 Bareacute J Pasmans F ClaeysM Bert W Haesebrouck F Houf K Martel A
SO WHY ARE SOME MICROBES PATHOGENIC AND OTHERS NOT (PROVIDED THERE IS A SUSCEPTIBLE HOST)
CASADEVALL MICROBE (2006)
AMOEBAE WORMS HEAT
SELECTIVE PRESSURES
ENVIROMENTAL MICROBES POSSESSTRAITS THA CAN FUNCTION IN VIRULENCE
THE CARDS OF VIRULENCE
MICROBIAL CARD lsquoHANDSrsquoONLY SOME lsquoHANDSrsquo CONFER PATHOGENIC POTENTIAL
MAMMALIANlsquoHANDrsquo
INSECTlsquoHANDrsquo
PLANTlsquoHANDrsquo
lsquoMARTIANHANDrsquo
lsquoNON-PATHOGENICrsquo
Microbe 2006
5152017
7
SOME PREDICTIONShellip
bull NEW FUNGAL DISEASES WILL APPEAR
bull FIRST EMERGENCE IN WARMER CLIMATES
bull FIRST EVIDENCE MAY COME IN COOLER MAMMALS
bull MORE PATHOGENIC BASIDIOMYCES
bull SOME MAY BE RESISTANT TO ALL ANTIFUNGALS
ASSESSMENT OF THREAT WOULD REQUIRE GREATER KNOWLEDGE OF FUNGAL BIOLOGY ECOLOGY THERMAL SUSCEPTIBILITY
COMPARISON OF VIRULENCE FOR THREE CRYPTOCOCCAL SPECIES
Cyptococcus podzolicus
Modified Findley K et al Eukaryotic Cell 8(3)353-361 2009
32 C39 C
34 CGALLERIA MELONELLA ALLOWS
LOWER TEMPERATURES
RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA
PHOSPHOLIPASE +UREASE +
BOTTOM LINE CONSISTENT WITH THE CONCEPT OF EMERGENCE THE PRESENCE OFVIRULENCE FACTORS WAS NOT PREDICTIVE FOR VIRULENCE
CAPSULE + CAPSULE +
MELANIN +
CAPSULE -
MELANIN -
C neoformans C amylolentus C podzolicus
EMBRACING THE X AXIS
THERE HAS BEEN LITTLE PROGRESS IN TREATING FUNGAL DISEASES IN A GENERATION WITH REGARDS TO REDUCING MORBIDITY AND MORTALITY ndash DRUGS ARE NOT ENOUGHT
5152017
8
BASIC RELATIONSHIP FOR lsquoDAMAGE-RESPONSE FRAMEWORKrsquo
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
Casadevall amp Pirofski Nature Micro Rev 2003
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
VIRULENCE IS A MICROBIAL PROPERTY THATIS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
ANTIBOTICSWORK PRIMARILY ON THE YAXIS BY REDUCINGINNOCULUM
IMMUNOMODULATION THE VIEW FROM THE DAMAGE-RESPONSE FRAMEWORK
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
ENHANCE
IMMUNITY
REDUCE
IMMUNITY
DISSEMINATED TB
ADD IFN-gTB MEINGITISADD STEROIDS
MYCOTIC DISEASES OCCUR AT BOTH HORNS OF THE PARABOLA
Aspergillus spp
DISSEMINATED
ASPERGILLOSISABPAASTHMASINUSITIS
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
6
A CASTELLANII SURFACE EXTRACT LABELS THE SURFACE OF SEVERAL PATHOGENIC FUNGI
UNPUBLISHED Gomes K X In Preparation
AMOEBA AND OTHER FUNGI
M anisopliaeB bassiana
Paracoccidioides brasiliensis
ILDINETE SILVA RIVERAPATRICIA ALBQUERQUELABORATORIES
Environ Microbiol Rep 2013 Dec5(6)819-24Interaction of Aspergillus fumigatus conidia with Acanthamoeba castellanii parallels macrophage-fungus interactionsVan Waeyenberghe L1 Bareacute J Pasmans F ClaeysM Bert W Haesebrouck F Houf K Martel A
SO WHY ARE SOME MICROBES PATHOGENIC AND OTHERS NOT (PROVIDED THERE IS A SUSCEPTIBLE HOST)
CASADEVALL MICROBE (2006)
AMOEBAE WORMS HEAT
SELECTIVE PRESSURES
ENVIROMENTAL MICROBES POSSESSTRAITS THA CAN FUNCTION IN VIRULENCE
THE CARDS OF VIRULENCE
MICROBIAL CARD lsquoHANDSrsquoONLY SOME lsquoHANDSrsquo CONFER PATHOGENIC POTENTIAL
MAMMALIANlsquoHANDrsquo
INSECTlsquoHANDrsquo
PLANTlsquoHANDrsquo
lsquoMARTIANHANDrsquo
lsquoNON-PATHOGENICrsquo
Microbe 2006
5152017
7
SOME PREDICTIONShellip
bull NEW FUNGAL DISEASES WILL APPEAR
bull FIRST EMERGENCE IN WARMER CLIMATES
bull FIRST EVIDENCE MAY COME IN COOLER MAMMALS
bull MORE PATHOGENIC BASIDIOMYCES
bull SOME MAY BE RESISTANT TO ALL ANTIFUNGALS
ASSESSMENT OF THREAT WOULD REQUIRE GREATER KNOWLEDGE OF FUNGAL BIOLOGY ECOLOGY THERMAL SUSCEPTIBILITY
COMPARISON OF VIRULENCE FOR THREE CRYPTOCOCCAL SPECIES
Cyptococcus podzolicus
Modified Findley K et al Eukaryotic Cell 8(3)353-361 2009
32 C39 C
34 CGALLERIA MELONELLA ALLOWS
LOWER TEMPERATURES
RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA
PHOSPHOLIPASE +UREASE +
BOTTOM LINE CONSISTENT WITH THE CONCEPT OF EMERGENCE THE PRESENCE OFVIRULENCE FACTORS WAS NOT PREDICTIVE FOR VIRULENCE
CAPSULE + CAPSULE +
MELANIN +
CAPSULE -
MELANIN -
C neoformans C amylolentus C podzolicus
EMBRACING THE X AXIS
THERE HAS BEEN LITTLE PROGRESS IN TREATING FUNGAL DISEASES IN A GENERATION WITH REGARDS TO REDUCING MORBIDITY AND MORTALITY ndash DRUGS ARE NOT ENOUGHT
5152017
8
BASIC RELATIONSHIP FOR lsquoDAMAGE-RESPONSE FRAMEWORKrsquo
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
Casadevall amp Pirofski Nature Micro Rev 2003
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
VIRULENCE IS A MICROBIAL PROPERTY THATIS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
ANTIBOTICSWORK PRIMARILY ON THE YAXIS BY REDUCINGINNOCULUM
IMMUNOMODULATION THE VIEW FROM THE DAMAGE-RESPONSE FRAMEWORK
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
ENHANCE
IMMUNITY
REDUCE
IMMUNITY
DISSEMINATED TB
ADD IFN-gTB MEINGITISADD STEROIDS
MYCOTIC DISEASES OCCUR AT BOTH HORNS OF THE PARABOLA
Aspergillus spp
DISSEMINATED
ASPERGILLOSISABPAASTHMASINUSITIS
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
7
SOME PREDICTIONShellip
bull NEW FUNGAL DISEASES WILL APPEAR
bull FIRST EMERGENCE IN WARMER CLIMATES
bull FIRST EVIDENCE MAY COME IN COOLER MAMMALS
bull MORE PATHOGENIC BASIDIOMYCES
bull SOME MAY BE RESISTANT TO ALL ANTIFUNGALS
ASSESSMENT OF THREAT WOULD REQUIRE GREATER KNOWLEDGE OF FUNGAL BIOLOGY ECOLOGY THERMAL SUSCEPTIBILITY
COMPARISON OF VIRULENCE FOR THREE CRYPTOCOCCAL SPECIES
Cyptococcus podzolicus
Modified Findley K et al Eukaryotic Cell 8(3)353-361 2009
32 C39 C
34 CGALLERIA MELONELLA ALLOWS
LOWER TEMPERATURES
RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA
PHOSPHOLIPASE +UREASE +
BOTTOM LINE CONSISTENT WITH THE CONCEPT OF EMERGENCE THE PRESENCE OFVIRULENCE FACTORS WAS NOT PREDICTIVE FOR VIRULENCE
CAPSULE + CAPSULE +
MELANIN +
CAPSULE -
MELANIN -
C neoformans C amylolentus C podzolicus
EMBRACING THE X AXIS
THERE HAS BEEN LITTLE PROGRESS IN TREATING FUNGAL DISEASES IN A GENERATION WITH REGARDS TO REDUCING MORBIDITY AND MORTALITY ndash DRUGS ARE NOT ENOUGHT
5152017
8
BASIC RELATIONSHIP FOR lsquoDAMAGE-RESPONSE FRAMEWORKrsquo
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
Casadevall amp Pirofski Nature Micro Rev 2003
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
VIRULENCE IS A MICROBIAL PROPERTY THATIS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
ANTIBOTICSWORK PRIMARILY ON THE YAXIS BY REDUCINGINNOCULUM
IMMUNOMODULATION THE VIEW FROM THE DAMAGE-RESPONSE FRAMEWORK
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
ENHANCE
IMMUNITY
REDUCE
IMMUNITY
DISSEMINATED TB
ADD IFN-gTB MEINGITISADD STEROIDS
MYCOTIC DISEASES OCCUR AT BOTH HORNS OF THE PARABOLA
Aspergillus spp
DISSEMINATED
ASPERGILLOSISABPAASTHMASINUSITIS
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
8
BASIC RELATIONSHIP FOR lsquoDAMAGE-RESPONSE FRAMEWORKrsquo
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
Casadevall amp Pirofski Nature Micro Rev 2003
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
VIRULENCE IS A MICROBIAL PROPERTY THATIS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
ANTIBOTICSWORK PRIMARILY ON THE YAXIS BY REDUCINGINNOCULUM
IMMUNOMODULATION THE VIEW FROM THE DAMAGE-RESPONSE FRAMEWORK
HOST RESPONSE
DISEASE THRESHOLD
WEAK STRONG
ENHANCE
IMMUNITY
REDUCE
IMMUNITY
DISSEMINATED TB
ADD IFN-gTB MEINGITISADD STEROIDS
MYCOTIC DISEASES OCCUR AT BOTH HORNS OF THE PARABOLA
Aspergillus spp
DISSEMINATED
ASPERGILLOSISABPAASTHMASINUSITIS
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
9
SOME PREDICTIONS
bull TECHNOLOGY WILL BECOME AVAILABLE THAT WILL ALLOW PHYSICIANS TO DETERMINE WHERE THE PATIENT IS ON THE DAMAGE-FRAMEWORK CURVE
bull THERAPY WILL EVOLVE FROM lsquoKILL THE MICROBErsquo TO lsquoHELP THE HOSTrsquo
bull INFLAMMATION WILL BE TITRATED FOR MAXIMAL ANTIFUNGAL EFFICACY AND MINIMAL HOST DAMAGE
bull FUNGAL DISEASES WILL BE TREATED WITH COMBINATIONS OF ANTIFUNGAL THERAPY AND IMMUNOTHERAPY
BUTTRESSING OUR INTERNAL DEFENSES TO REDUCE FUNGAL DISEASES
Enhancing the Symbiont
0
02
04
06
08
1
12
4 12 15 18 21 25 30 35 37 40 42 45
S eries 2
y = -00616x + 279110
02
04
06
08
1
30 32 34 36 38 40 42 44
Temperature
Perc
en
t g
row
th t
ole
ran
t
THERMAL TOLERANCE OF gt4000 FUNGI
PHYSICAL DEFENSE TEMPERATURE
Robert amp Casadevall JID 2009 Vincent Robert
THERAPEUTIC FEVERS
Give me the power to produce feverand I will cure all diseasesrsquo
Hippocrates
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
10
FOR DIFFICULT MYCOTIC DISEASES
DIAGNOSIS
THERMAL SUSCEPTIBILITY
gt 41 oC lt 41 oC
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
TARGET TEMPERATURE
ANTIFUNGAL THERAPY
IMMUNOTHERAPY
FEVER THERAPY
MICROBIOME MANIPULATION
FOCUS ON SUSCEPTIBLE INDIVIDUALS
bull FUNGAL INFECTIONS ARE EXTREMELY COMMON BUT DISEASE IS RARER
bull AMONG SUSCEPTIBLE POPULATIONS ONLY A FEW INDIVIDUALS SUFFER DISEASE
bull INDIVIDUAL SUSCEPTIBILITY A COMPLEX FUNCTION OF GENETICS HISTORY MICROBIOME IMMUNITY
bull STRATIFYING RISK WILL MAKE FUTURE ANTIFUNGAL STRATEGIES MORE EFFECTIVE
STRATIFYING SYMBIONTS FOR RISK WILL ENABLE
bull VACCINATION
bull IMMUNOTHERAPIES (ANTIBODY CYTOKINE ETC)
bull MICROBIOME INTERVENTIONS
bull TARGETED ANTIFUNGAL PROPHYLAXIS
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW
5152017
11
IN DIAGNOSTICShellip
bull CONTINUED IMPROVEMENTS OVER NEXT DECADE
bull THENhellipA REVOLUTION WILL OCCUR WHEN NMR CAN DETECT FUNGAL MATERIAL IN VIVO
LAST PREDICTIONS
bull MEDICAL MYCOLOGY WILL EVOLVE INTO A MORE HOST-FOCUSED DISCIPLINE
bull THERE WILL BE GRADUAL BUT SIGNIFICANT IMPROVEMENTS IN PROGNOSIS AS BASIC MICROBIOLOGIC GENETIC AND IMMUNOLOGICAL KNOWLEDGE IS BROUGHT TO THE BEDSIDE
bull MEDICAL MYCOLOGY WILL INCREASE IN IMPORTANCE RELATIVE TO WHERE IT IS NOW