Update TRENDS in Microbiology Vol.11 No.
4 April 2003 157
| Letters
Microbial virulence results from the interaction
between host and microorganism
Arturo Casadevall and Liise-anne Pirofski
Department of Medicine and Department of Microbiology and Immunology, The Albert Einstein College of Medicine,
1300 Morris Park Ave, Rm 709 Forchheimer Bldg., Bronx, NY 10461, USA
For too long investigators interested in the phenomenon of
virulence have focused on microbial characteristics hoping
to explain why some microorganisms are virulent whereas
others are not. Hence, much of the pathogenesis-related
research of the past decade, and the terminology used to
describe pathogenesis and infectious diseases, arose from
an intellectual milieu that was driven by the premise that
microbial virulence was a unique microbial attribute.
However, as virulence is a microbial characteristic that
can only be expressed in a susceptible host, it cannot
possibly be considered an independent microbial attribute
[1]. Even pathogenic microorganisms such as Clostridium
tetani and Corynebacterium diphtheriae, for which viru-
lence is attributed to a toxin, do not cause disease in
immunized hosts. The paper by Romani et al. published in
the November issue of Trends in Microbiology brings a
welcome balance to the field of microbial pathogenesis by
suggesting that fungal virulence, and specifically the viru-
lence of Candida albicans, results from the interaction of
fungal cells with dendritic cells (DCs) [2]. These investi-
gators have reported that the outcome of C. albicans
infection (i.e. disease vs commensalism) could be a func-
tion of the host immune response that occurs upon the
interaction of DCs with Candida hyphal or yeast forms.
They have put forth the hypothesis that host products
(e.g. cytokines) produced in response to the interaction
between certain microbial components and different DC
receptors determine whether the outcome of infection will
be disease or commensalism. This establishes the host as a
required and equal partner in virulence. In essence, these
investigators have redefined the approach to and charac-
terization of Candida virulence mechanisms by focusing
on the nature and immunological outcomes of the inter-
action of host DCs with Candida ligands. This is a major
contribution to the field.
Virulence factors and strategies have been difficult to
define for many pathogens of humans, including C. albicans.
In our view, a precise lexicon that is based upon the out-
comes of host –microorganism interactions is a necessary
component for understanding the phenomena of virulence
and microbial pathogenesis. For many pathogens, and for
C. albicans in particular, the terminology used to describe
the state of host– pathogen interaction is often ambiguous
and imprecise. For example, the term ‘infection’ is often
equated with the ‘disease’ candidiasis, and Candida is
often described by the adjective ‘opportunistic’, despite the
Corresponding author: Liise-anne Pirofski (pirofski@aecom.yu.edu).
http://timi.trends.com
fact that vaginal candidiasis can occur in otherwise healthy
women. However, a major problem with the application of
such ‘infection-based’ terminology to Candida pathogene-
sis is that it is unable to account for why disease occurs in
some, but not most, individuals. Moreover, equating the
terms ‘infection’ and ‘disease’ can cause confusion because
they are not synonymous [3]. Other examples of conditions
where ‘infection’ is not synonymous with ‘disease’ include
HIV infection before the onset of symptomatic disease and
primary tuberculosis, conditions where the organism exists
in the host without causing symptoms or clinical illness.
Hence, this usage might hinder progress in understanding
the pathogenesis of disease (reviewed in [3]).
Recently, we characterized the lexicon of microbial
pathogenesis by six terms: exposure, infection, coloniz-
ation, commensalism, latency and disease [4]. Each term
reflects an outcome of the host – microorganism inter-
action, with colonization, commensalism, latency and
disease being defined by the amount and nature of host
damage resulting from this interaction. To the extent that
both commensalism and colonization cause no perceptible
damage to the host, they are synonymous terms [4].
According to this proposal, it is possible to simplify the
characterization of the states of host– C. albicans inter-
action without the use of imprecise terms such as oppor-
tunism and saprophytism, and to focus on the interactions
that do or do not result in clinically relevant outcomes. For
C. albicans, acquisition of the organism occurs shortly
after birth when the neonate is exposed to the organism
through human contact. We have termed the process of
acquisition of an organism by a host as ‘infection’, con-
sistent with the original derivation of the word [4]. The
initial infection can either lead to disease in the form of
neonatal candidiasis or to colonization and/or commen-
salism [3]. Acquisition of C. albicans by the host, or
‘infection’, is accompanied by a host response, as indicated
by the presence of antibodies to candidal antigens in young
children [5]. It is generally thought that the antibody
response to Candida antigens establishes part of the
repertoire of ‘naturally occurring’ antibodies, and that the
presence of Candida and other organisms in the human
gastrointestinal tract foils the pathogenic strategies of
other (more invasive) microbial pathogens.
The states of Candida colonization and commensalism
are largely indistinguishable, as for the majority of healthy
humans the presence of C. albicans causes no host or
microbial damage and does not lead to elimination of the
organism. However, the organism is not eliminated by the
158 Update TRENDS in Microbiology
normal host over time and there are possible symbiotic
benefits to both host and microorganism. Hence, the
outcome of Candida infection is generally considered to
be commensalism, unless there is evidence for a newly
acquired infection [3]. By contrast, Candida-mediated
disease (e.g. candidiasis) can result if the state of
commensalism is disturbed, primarily by factors that
damage mucosal surfaces or mediate immune defects, such
as antibiotic use, intravenous catheters, mucosal break-
down or HIV infection. The model proposed by Romani
et al. [2] is a significant advance in the field, because it
provides a testable hypothesis that incorporates contri-
butions from both the microorganism and the host into
paradigms to explain the pathogenesis of Candida-
associated diseases. Hence, the model is consistent with
the ‘damage-response framework’ [1,3,4,6], in that it
attributes Candida virulence to the outcome of the host
DC receptor–microbial component interaction. The full
range of outcomes of host –Candida interaction can be
accommodated and explained by the damage or lack of
damage to the host, and/or the ensuing host response
resulting from this interaction. Interplay between Candida
and the host takes place throughout the life of the host, but
disease is most common at a time when the adaptive
immune response has been established. Therefore, the
| Letters Response
Response from Romani et al.: Microbial virulence
results from the interaction between host and
microorganism
Luigina Romani, Francesco Bistoni and Paolo Puccetti
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
We are grateful to Drs Casadevall and Pirofski for their
interest and comments on our recently published Opinion
article [1] and would like, in turn, to offer a brief comment
further addressing the important issues they have raised.
Needless to say, we agree with the point repeatedly made
by Drs Casadevall and Pirofski that there are major
conceptual differences between infection and disease,
particularly in the case of microorganisms that are com-
mensals [2 – 4]. In the case of fungi, most, if not all, fungal
species do not cause severe disease in intact hosts and the
major expression of virulence for most fungi occurs under
conditions of impaired immunity. Therefore, it appears
that host immunity can be considered a functional attri-
bute of fungal virulence that can apply to varying degrees
in different fungal species. We have proposed a mechanism
of fungal recognition and handling by the host’s immune
system that can operate at different body sites, eventually
leading to different fungus – host relationships. Certainly,
Corresponding author: Luigina Romani (lromani@unipg.it).
http://timi.trends.com
Vol.11 No.4 April 2003
model presented by Romani et al. might be more directly
applicable to primary C. albicans infection, when the
host –microorganism interaction is initiated by the first
contact between a naive host and fungal cells early in
infancy, than to the host– microorganism interactions
that occur later in life and can lead to diseases such
as candidiasis.
References
1 Casadevall, A. and Pirofski, L. (2001) Host – pathogen interactions: the
attributes of virulence. J. Infect. Dis. 184, 337– 344
2 Romani, L. et al. (2002) Fungi, dendritic cells and receptors: a host
perspective of fungal virulence. Trends Microbiol. 10, 508 – 514
3 Casadevall, A. and Pirofski, L. (2002) The meaning of microbial
exposure, infection, colonisation, and disease in clinical practice. Lancet
Infect. Dis. 2, 628 – 635
4 Casadevall, A. and Pirofski, L. (2000) Host – pathogen interactions: the
basic concepts of microbial commensalism, colonization, infection, and
disease. Infect. Immun. 68, 6511 – 6518
5 Goldman, D.L. et al. (2001) Serologic evidence for Cryptococcus infection
in early childhood. Pediatrics 107, E66
6 Casadevall, A. and Pirofski, L. (1999) Host – pathogen interactions:
redefining the basic concepts of virulence and pathogenicity. Infect.
Immun. 67, 3703 – 3713
0966-842X/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0966-842X(03)00008-8
fungi that are commensals in humans are easier to accom-
modate within this framework than free-living fungi,
although a similar degree of intricacy among morpho-
genesis, pathogenicity and receptors has been seen with
Aspergillus, which is a true saprophyte [5].
The important concept is that, although effector
phagocytes undoubtedly contribute to the balance between
protection and virulence, only dendritic cells (DCs) are
central to the balance between immunity and virulence [6],
through their functional plasticity. Host reactivity result-
ing from the interaction between certain fungal morpho-
types (and possibly certain microbial components) and
different DC receptors might determine the outcome of
infection, be it disease or commensalism. The important
issue here is whether (and which) tissue-dependent factors
would be crucial in dictating the pattern of receptor
engagement on DCs and the consequent occurrence of a
state of protection, non-protection or tolerance. It is
interesting that regulatory T cells are selectively induced
by contact with Candida albicans in the gut but not in the