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

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

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

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

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

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

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