Fungal virulence, vertebrate endothermy, and dinosaur extinction:
is there a connection?
Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
Department of Microbiology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
Received 14 November 2004; accepted 30 November 2004
Fungi are relatively rare causes of life-threatening systemic disease in immunologically intact mammals despite being frequent
pathogens in insects, amphibians, and plants. Given that virulence is a complex trait, the capacity of certain soil fungi to infect,
persist, and cause disease in animals despite no apparent requirement for animal hosts in replication or survival presents a paradox.
In recent years studies with amoeba, slime molds, and worms have led to the proposal that interactions between fungi and other
environmental microbes, including predators, select for characteristics that are also suitable for survival in animal hosts. Given that
most fungal species grow best at ambient temperatures, the high body temperature of endothermic animals must provide a thermal
barrier for protection against infection with a large number of fungi. Fungal disease is relatively common in birds but most are
caused by only a few thermotolerant species. The relative resistance of endothermic vertebrates to fungal diseases is likely a result
of higher body temperatures combined with immune defenses. Protection against fungal diseases could have been a powerful selec-
tive mechanism for endothermy in certain vertebrates. Deforestation and proliferation of fungal spores at cretaceous–tertiary
boundary suggests that fungal diseases could have contributed to the demise of dinosaurs and the flourishing of mammalian species.
? 2004 Elsevier Inc. All rights reserved.
Keywords: Fungi; Pathogenic; Endothermy; Ectothermy; Dinosaur; Amoebae
Of the more than 1.5 million estimated fungal species
(Hawksworth, 2001), only about 150 cause disease in
mammals and of these species only a few are common
pathogens (Kwon-Chung and Bennett, 1992). With the
exception of the dermatophytes, which are common
causes of skin infection and disease in many mammalian
species, systemic fungal diseases are relatively rare in in-
tact mammals compared to those caused by bacteria and
viruses. In humans, systemic fungal diseases were con-
sidered a rarity until the mid-20th century, when
drugs, indwelling venous catheters, and immunosup-
pressive therapies. In fact, fungal diseases such as cryp-
tococcosis, blastomycosis, and histoplasmosis were not
described until the late 19th century when advances in
laboratory science led to more detailed pathological
descriptions in unusual cases of disease. For example,
Cryptococcus neoformans was not associated with hu-
man disease until 1894 (Knoke and Schwesinger,
1994). In contrast, tuberculosis, smallpox, plague, and
many other infectious diseases were known since antiq-
uity. Presumably, this reflects the relative infrequency of
systemic fungal diseases in human populations such that
the occasional cases that must have occurred before
modern times were not recognized as a distinct disease
entity worthy of description. Today systemic fungal dis-
eases are common but most occur in individuals with
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Fungal Genetics and Biology 42 (2005) 98–106
impaired immunity as a consequence of HIV infection,
immunosuppressive drugs, integument compromise by
catheters and surgery, and disruption of host commen-
sal bacterial flora by antimicrobial drug use. Hence, hu-
mans as a species appear to be remarkably resistant to
fungal diseases except in conditions where host defenses
Comparisons of the relative frequency of fungal dis-
ease across species are difficult because we lack incidence
and prevalence data for the overwhelming majority of
animal species. However, there is sufficient information
emerging in the literature to begin to assemble general-
izations and consider hypothesis that are potentially
testable. In common with the rarity of human mycoses,
systemic fungal diseases appear to be relatively infre-
quent in other mammals such as rabbits, rodents, cats,
and dogs, although some dog breeds are susceptible to
blastomycosis and cryptococcosis occurs frequently in
Koala bears (Canny and Gamble, 2003; Connole
et al., 2000; Kerl, 2003; Krockenberger et al., 2003; Pol-
lock, 2003). Some birds appear to be susceptible to sys-
temic fungal diseases and Aspergillus fumigatus is a
relatively common pathogen. Approximately 20% of
immature loons succumb to respiratory fungal disease
(Sidor et al., 2003) and aspergillosis is common in tur-
keys and stitchbirds (Cork et al., 1999; Lair-Fulleringer
et al., 2003). In contrast to mammals, fungi are fre-
quently associated with disease in ectothermic organ-
isms such as plants, insects, fish, and amphibians. For
example, chytridiomycosis has been implicated in the
worldwide decline in amphibian populations (Berger
et al., 1998; Daszak et al., 1999) and fungi are common
pathogens of mites (van der Geest et al., 2000). Fungal
diseases may also be critical contributors to the world-
wide decline in coral reefs (Rosenberg and Ben Haim,
2002). Two questions emerge from these observations:
(1) Why are some fungi virulent for mammals? and (2)
Why are most mammals relatively resistant? In ponder-
ing these questions some insights emerge that could be
relevant to the unsolved problems of the origins of ver-
tebrate endothermy and the causes of past extinctions.
2. Virulence and pathogenicity
Before analyzing the specific attributes of fungi as
pathogenic microbes it is worthwhile to consider the def-
initions of virulence and pathogenicity, since these are
central elements in any discussion of fungal pathogene-
sis. Virulence is a microbial attribute that is expressed
only in the context of a susceptible host, and conse-
quently, it is not an independent microbial property
(Casadevall and Pirofski, 2001). Although various defi-
nitions for virulence have been proposed over the years,
I believe that virulence is best defined as the relative
capacity of a microbe to cause damage in a host (Casa-
devall and Pirofski, 1999). This definition is broadly
inclusive of the enormous diversity of host–microbe
interactions and grounds the term virulence on host
damage, a relevant outcome to the host. Host damage
can result from microbial processes, the host immune re-
sponse or both, and disease occurs when host damage
interferes with homeostasis (Casadevall and Pirofski,
1999). The realization that damage is the relevant host-
related outcome in the host–microbe interaction led to
the development of the ?damage–response framework?
of microbial pathogenesis (Casadevall and Pirofski,
1999, 2000, 2003). This framework is grounded on three
observations: (1) microbial diseases result from the inter-
action of two entities, a host and a microbe; (2) host
damage is the relevant outcome of the host–microbe
interaction; and (3) host damage can ensue from the di-
rect action of microbial factors, the immune response, or
both (Casadevall and Pirofski, 1999, 2000, 2003). When
damage is considered as a function of the immune re-
sponse for host–microbe interactions it is apparent that
the basic relationship is usually parabolic with maximal
damage occurring in situations of weak or strong im-
mune responses. The ?damage–response framework? of
microbial pathogenesis describes six basic types of inter-
actions that allow the grouping of human pathogenic mi-
crobes into six Classes based on the average outcome of
their interaction with certain hosts rather than phyloge-
netic differences (Casadevall and Pirofski, 1999). Since
human systemic fungal diseases occur primarily in hosts
with impaired immune function most human fungal
pathogens such as Candida albicans, Cryptococcus neo-
formans, and Blastomyces dermatitidis have been catego-
rized as Class 1 and 2, categories that include many other
non-fungal pathogens (Casadevall and Pirofski, 1999).
However, some fungal diseases occur as a consequence
of strong host responses and Histoplasma capsulatum
and Aspergillus spp. were classified as Class 3 and 4,
respectively, which also include bacteria and viruses
(Casadevall and Pirofski, 1999). Hence, the ?damage–re-
sponse framework? makes no distinction among patho-
genic microbes based on phylogenetic origin and shows
no fundamental difference between fungi and other types
3. The rarity of life-threatening fungal diseases in
immunologically intact mammals
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by transmission from other hosts. This group includes
Candida spp. and a few other fungal species such as
Malassezia (Ashbee et al., 2002). Commensal fungi are
adapted to their hosts and systemic disease is almost
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