Emerging Infections: An Evolutionary Perspective

Joshua Lederberg, The Rockefeller University, New York, New York, USA

[Emerging Infectious Diseases 4(3):366-371, 1998. Centers for Disease
Control]

Introduction

Our relationship to infectious pathogens is part of an evolutionary
drama[1]. Here we are; here are the bugs. They are looking for food;
we are their meat. How do we compete? They reproduce so quickly, and
there are so many of them. They tolerate vast fluctuations of
population size as part of their natural history; a fluctuation of 1%
in our population size is a major catastrophe. Microbes have enormous
potential mechanisms of genetic diversity. We are different from them
in every respect. Their numbers, rapid fluctuations, and amenability
to genetic change give them tools for adaptation that far outpace
what we can generate on any short-term basis.

So why are we still here? With very rare exceptions, our microbial
adversaries have a shared interest in our survival. With very few
exceptions (none among the viruses, a few among the bacteria, perhaps
the clostridial spore-forming toxin producers), almost any pathogen
reaches a dead end when its host is dead. Truly severe host-pathogen
interactions historically have resulted in elimination of both
species. We are the contingent survivors of such encounters because
of this shared interest.

Microbial Resources

Intraclonal Processes

DNA Replication. Microbial intraclonal methods of variation are
legion. DNA replication is error prone, and often the constraints of
precise replication are turned off in the presence of DNA damage or
other injury. Microbes often live in a sea of mutagens, chemical and
physical. If we go out in the sun, our skin is damaged; in microbes,
UV irradiation goes unimpeded to the very core of their DNA. Those
that are not killed are rapidly mutated.

RNA Replication. RNA replication is particularly error prone. There
are no editing mechanisms for examining the fidelity of replication;
therefore, the concept of the quasispecies swarm was recently
generated. For many RNA viruses, retroviruses in particular, the
rates of mutation are so high that to a close approximation, every
particle is genetically different (in at least one nucleotide) from
every other particle. They are rapidly evolving as swarms of
genotypes, no single genotype being totally representative. Natural
selection plays a substantial role. The role of cooperativity in
infection of these viruses, particularly among retroviruses and HIV,
has not been adequately investigated. Rous sarcoma virus is a case in
point. It may be difficult for a single particle, many generations
removed from the original competent infector, to consummate an
infection by itself, but it can be complemented by other helper
viruses present in the same cell.

Haploid Organisms. Most of the organisms we are dealing with are
haploid, so they have no delay in expressing new genetic factors. The
prompt expression may potentially augment cumulative genetic
alterations, but in the short run, a resistance mutation will
manifest itself almost immediately and will be subject to natural
selection very promptly. Multicopy plasmids, which would behave
differently, are exceptions.

Phase Variation. Phase variation occurs in almost every pathogenic
bacterium, in malaria parasites, in trypanosomes, and in Borrelia.
Changes that appear to be mutational, on closer examination turn out
to be microbial access to an archive of genetic information, much of
which has been silenced and then reappears as an adaptive change. The
flagellar antigens of salmonella provide the historic example; they
can exist in either so-called specific phase or group phase, going
back to H1 or H2 loci. We now know that they are the result of
silencing one of these loci by the position of a piece of DNA that
can be inverted to move the promoter from one locus to another and
give a very sudden transformation of the serotype from type 1 to type
2. This is a completely reversible phenomenon; the same event can
reinvert that DNA. Many species of site-specific recombinases are
capable of scrambling and rescrambling the bacterial genome in order
to silence and unsilence genes that may be then carried in an
archival state. I pondered why bugs use this mechanism for keeping
genes in a cryptic state when gene expression can be (and often is)
regulated in other ways. The simplest speculation is that phase
variation very often entails controlled antigenic factors. A bug does
not want to telegraph to its host in advance that it is carrying even
a tiny relic of an alternative epitope because that will provoke
immunity on the part of the host even before it has undergone that
phase variation.

Genetic factors also control the rates of mutability; whether these
factors do or do not directly influence adaptability to virulence is
controversial. Preliminary reports suggested that virulent bacteria
had a higher incidence of mutators. We now realize that mutators are
quite prevalent, and therefore bacteria are constantly facing
environmental challenges.

Interclonal Processes

Recombination mechanisms are quite promiscuous. Conjugation, which
can occur between bacteria of widely varying kinds, is most often
recognized by plasmid transfer and every now and then by mobilization
of chromosomes. Conjugation can even occur across kingdoms, between a
bacterium and a yeast, or between a bacterium and a plant. In the
case of the rhizobium-like parasite, the crown gall bacterium,
genetic material is transferred from the bacterium into the
chromosomes of the host plant. Similar phenomena probably occur in
eukaryotic infections. Some genes in viruses and bacteria almost
certainly were of eukaryotic origin. Some bacteria can deliver DNA
intercellularly to their host animals.

Plasmid interchange (movement of tiny bits of DNA from one species to
another) is not just a laboratory curiosity; it is the mechanism for
rapid spread of antibiotic resistance from widely different species,
one to another. It adds even greater cogency to our concerns about
the less than optimally advantageous use of antibiotics (e.g., in
animal husbandry). The mechanisms exist to make it easy not only for
single antibiotic resistance but whole blocks of resistance to be
moved from one bacterium to another.

Host-Parasite Coevolution

Microbes' shared interest in our survival will dominate the overall
picture of their evolution. Can this help us predict the outcome of
the balance between the host and the pathogen? The possible outcomes
are so divergent that it is very difficult to predict in detail what
is going to happen in any particular confrontation.

The long-term trend is coadaptation, in which the host acquires
factors for resistance and the parasite acquires factors for
mitigation and longer survival of (and thereby in) the host. These
factors may be genetic mutations, which will certainly be selected.

Other factors include human cultural changes, such as hygienic
procedures. The human species outdoes all other species in adopting
behavior that is self-destructive rather than self-protective. I am
not convinced that every nuance of human behavior has been
specifically evolved. Most of our behavior, even the maladaptive
self-destructive kind, is learned: the pity and the hope of our
species.

Pathogens find it to their advantage to mitigate their virulence,
provided they can do so without compromising their livelihood. That
is the tightrope they walk. Rhinovirus, the agent of the common cold,
is an extremely successful pathogen. We do little to get rid of it.
We go to work and school with our runny noses. The virus has a number
of adaptations (including the very moderation of its disease process)
that tend to facilitate its spread. I worry that a rhinovirus may
some day mutate into a somewhat more virulent form, given that it is
capable of very rapid spread.

Evolutionary Strategies

The parasite's dilemma is that if it proliferates rapidly, it may
kill the host; that would be a winning strategy if transmission were
easy, vectors readily available, the host's behavior obliging, and
mosquitoes abundant for high-density spread. Such circumstances are
present in northwest Thailand where Plasmodium falciparum would be
unlikely to survive for very long (because of its profound effects on
its host) if the density of spread to new hosts were not favorable.
In modern hospitals, the mosquitoes are health-care attendants who
inadvertently facilitate the transfer of infection from one patient
to another.

Toxins

It is a wonder that the inexhaustible reservoir of potent toxins has
not spread much further. Botulinum toxin, one of the deadliest
compounds, is produced in abundance by Clostridium botulinum, whose
spread to other organisms and potential for becoming a major public
health threat can easily be imagined. Why is this toxin so confined?
The underlying biologic mechanisms are not confining it; rather, its
lethality keeps it under control. The microbe kills its host rapidly,
and if it cannot continue to multiply even in the dead host, it
reaches a dead end.

In specific physiologic circumstances, these rules of natural
selection might not apply. Escherichia coli O157 is a case in point.
O157 has little to do with E. coli; it is a shigella with a little
cloak of E. coli antigens. O157 should not be used as the sole
diagnostic criterion for the spread of shigelloid disease. The toxin
genes can inhabit other vectors. The ecologic implications of its
human and bovine virulence are not clear. Perhaps polymorphism
(changes in bacterial genotype) alters its virulence in human and
bovine species. The human loop is quite incidental to its overall
survival, as far as we know. The attack rate in humans is only 1%.
How has E. coli O157 evolved? We understand that as poorly as we
understand the sporadic emergence of Legionella from the soil into
our air-conditioner ducts.

Proliferation Rate

If the parasite adopts another strategy and proliferates slowly, we
have an evolutionary mechanism in which our own immune system is
looking for deviants; this mechanism will be presenting new epitope
receptors waiting to be stimulated. Most acute infections produce a
full immune response at a humoral and a cellular level within a week
or 10 days. So the microbe that proliferates slowly is laying the
groundwork for its own vulnerability unless it adopts some further
tactics (e.g., phase variation, stealth tactics, antigenic mimicry,
exploiting the autotolerance that the host needs to survive its own
immune system). Parasites also compete with commensals, with
probiotic organisms. This is where HIV runs into severe trouble. Left
to its own devices, HIV would not kill its host; but by knocking down
the host's immune system, the virus opens the door for other
organisms, including commensals, opportunists that can thrive only
when the immune defenses are attenuated.

Symptoms

Vectors are rarely symptomatic, almost never severely symptomatic.
The plasmodium would not benefit from killing the mosquitoes that
transmit it. If a rabid dog can be considered a vector, its
behavioral anomaly illustrates another adaptation that serves the
purposes of the parasite.

This line of thinking, what some people have called evolutionary
medicine (call it common sense) leads us to look at symptoms. To what
extent should we be treating them? Some we treat because they are
life-threatening. But is fever, for example, a host defense? Is it a
mode of bacterial attack? Is the bacterium or virus producing
pyrogens because a higher temperature will promote its own
replication? Are pyrogens just side effects of other evolutionary
adaptations that have not come to equilibrium? It is hard to avoid
models that assume equilibrium; few complex physiologic systems are
so obliging. We should question symptoms from an evolutionary
perspective. How did they come to be there? This approach may open
the door to new avenues of thought in examining the disease process.
Cough, diarrhea, or hemorrhage may serve the purposes of the
parasite; even so, we may still have to treat hemorrhage, but how far
should we go in treating cough? On the one hand, if not too severe,
cough may eliminate some of the infectious load from the body; on the
other hand, cough generates an aerosol that further disseminates the
organism. Cough may have to be treated as a public health measure as
much as a therapeutic measure. Diarrhea is another example; it may be
a way of eliminating the parasite or a special adaptation enhancing
dissemination.

Other symptoms (malaise, headache, pain, itching) probably have
different answers. Pain is a puzzling symptom, which plays an
indispensable role by drawing attention to a disease. Once the
disease is acknowledged, there is no reason in the world not to treat
pain. Yet I know of no infection (other than chronic leprosy) that
induces anesthesia. It would seem to me that a microbe bent on
thriving would impart a sense of euphoria (rather than pain) to its
host; we would welcome it and infect ourselves with it. Analgesia may
be the eventual moral hazard of biotechnology, the internalized
moonshine still or poppy patch.

The ultimate symptom, death of the host, is almost never to the
advantage of the parasite. Death signals a breakdown in the
equilibrium (the contract between parasite and host) that could have
had a better outcome had both sides been more witting.

Zoonotic Interactions

Many lessons of evolutionary relationships come from zoonotic
interactions. Infections that break out of their host of origin often
have a very severe impact on their new host. Hantavirus is an
outstanding recent example. The pathologic processes in the rodent
carriers hardly compare with those in humans. Most zoonotic transfers
simply do not work. They are host specific; many are neutral. Every
now and then, a zoonotic transfer has enormously larger pathologic
implications for the host; these are the transfers we focus on. We
presume that the filoviruses and perhaps HIV are in that category.
Many, not all, simian immunodeficiency viruses are perceptibly less
virulent in their natural host than HIV is in humans, perhaps another
example of equilibrium breakdown.

How could the zoonoses be pathogenic when they require so many subtle
adaptations to come into a host and really cause disease? Dozens, if
not hundreds, of bacterial genes would have to work in concert to be
pathogens. Microbes make proteins and carbohydrates, familiar to our
systems of immunity. Therefore, if the parasite does not know how to
live in the earthly host and the host cannot cope with totally alien
parasites, we end up with a wash.

Consider tsutsugamushi fever, scrub typhus. Bangkok is reporting
intermediate levels of drug resistance in Orientalia in tsutsugamushi
in central and eastern Thailand. The life cycle is one of essentially
a hereditary symbiont; the tick is transmitted transovarially and can
be communicated from tick to microbe or humans, where it rapidly
proliferates. Reinfection back to the tick is not of consequence,
which must be a fairly recent spillover of pathogenicity for which
there is not ongoing selection. Nothing in the life history of
Orientalia would sustain its pathogenicity to maintain its high
infectivity.

Years ago planetary quarantine became a policy consideration,
beginning with Sputnik in the late 1950s and the early planning of
our space program. Would it be permissible to move contaminated
spacecraft from one planet to another? Certainly proliferating
organisms on Earth could be easily carried to Mars. What would happen
if we brought back Mars samples? These considerations resulted in an
international convention for the conservation of the microbial
virginity of celestial bodies. Sterilization protocols were applied
to the Viking Mars spacecraft and by the Russians in the 1970s.

Maternal Immunity

One mechanism of accommodation is not genetic but physiologic:
maternal immunity. The recent outbreak of canine distemper in the
lions of the Serengeti[1] demonstrates a quasihereditary cycle that
does not involve the genes at all but rather is the propagation of
maternal immunity, partial immunity on the part of the offspring,
easier adaptation to infection by the host.

Mitochondria -- the Ultimate Pathogens

What are the ultimate pathogens, the ultimate symbionts? The
mitochondria. A bacterial invader probably 2.5 billion years ago got
into the first eukaryotic cells and conferred oxidative machinery.
Who is serving whom? We generally think mitochondria are to our
advantage, but think how hard we work to shovel the coal into the
furnace that the mitochondria have provided in every cell of our
body. Symbiosis is a fact of life, not always friendly or mutually
accommodating. In bacteria, plasmids confer great advantages for some
functions, but many plasmids also convey a "leave me and you die"
message. The plasmid encodes simultaneously for a toxin and an
antitoxin but makes sure that the toxin has a longer lifespan. So a
bacterium careless enough to drop its plasmid will suffer. The
plasmid has the long-term advantage of ensuring that only cells able
to continue to proliferate will continue to have the plasmid. So
knowing who is serving whom in these kinds of relationships is very
complicated.

Patterns of Evolution

Thanks to the wonders of genomics and DNA analysis, we have a good
overall model of the tree of life and the overall patterns of
evolution. By the criterion of 16S RNA, extraordinary evolutionary
changes have occurred within the multicellular branch, but these
changes are not at the level of fundamental housekeeping machinery;
they have to do with growing brains, eyes, branches, and flowers,
incidental items not at the level of cellular physiology.

Viruses

Where do viruses come from? Certainly in the world of eukaryotic
viruses, no one can say with confidence what the evolutionary
provenance is. We believe that viruses originated from some kind of
cellular organelle, perhaps ultimately from the nuclear DNA, perhaps
from the other organelles. Many of them would have to have undergone
enormous changes, and we cannot say which came from where in any
tangible example. This complexity can be illustrated (in the
prokaryotic systems) by the ease with which viral genomes can be
integrated into bacterial chromosomes. These are all double-stranded
DNA bacterial viruses, so they have the same fundamental structure as
bacterial chromosomes. They go in and out with ease and can be
integrated and mobilized, sometimes as viruses, sometimes as
bacterial genes. It is impossible to say which came first. If one
could point to an evolutionary progression of clusters of genes in a
bacterium on the way to generation of a new virus, it would be of
some help, but how would one know it was not the relic of a very old
one coming back again? Our most fundamental knowledge is very
primitive.

Prions

Prions offer a new paradigm, much of which we do not understand. Stan
Prusiner has argued that prions are pure proteins. Trying to
understand how a pure protein can propagate confounds our conceptions
of the transmission of biological information. So let us say that
prion protein (e.g., scrapie prion protein) is a conformational
modification of a normal protein, prp-c, coded for by an endogenous
gene, a part of the normal genome, not an essential gene. Infected
mice show some functional disorders but can survive. One might argue
that we do worse with this gene than without it as long as we are
susceptible to this modification.

Not much new sequence information is imparted to the normal prion to
convert it to the infective agent. The change may be merely in the
prion's conformation. We must consider other mechanisms that might
cause that same conversion.

The rare nonfamilia incidence of sporadic Creutzfeldt-Jakob disease
(CJD) poses a possible example, although it is difficult to exclude
some contact with prions in individual cases. We might watch for
CJD-like disease as an incident to other kinds of toxic insults. One
implication of the protein-prion model, not discussed hitherto, is
that conformer alterations may ensure from chemical or physical
trauma to preexisting prp-c; heat, toxins, side effects of other
infections are candidates[2]. Let us carefully label this as wild
speculation, pending badly needed assays for this conformer-altering
capacity. Other protein-aggregate or amyloid-based diseases (like
Alzheimer's) likely have a nucleating episode in their pathogenesis,
even if there is no means of contagion from one person to another. At
least in the pancreas, amyloid aggregation is a side effect of
protein injury by glycation[3].

Emerging Pathogens

What are we going to do about new, mutant, and recombinant pathogen
strains? What can we anticipate about new major outbreaks? How should
we be defending ourselves? The good news of course is the wonderful
technology in the offing, one marvelous innovation after another in
every field of prophylaxis, vaccines, understanding of pathogenic
phenomena. The genomics work on bacteria is paying off and may even
justify the overall project of human genomics all by itself with its
insights into microbial evolution and potential targets for new
discoveries in disease management.

At a very high strategic level, we have the basic knowledge to
control foodborne epidemics, waterborne epidemics, and fecal-borne
diseases. At a technologic level, even sexually transmitted diseases
can be controlled. One neglected medium is air. Can we do as well in
preventing airborne transmission? Effective control may come down to
something as elementary as a face mask like that worn by police in
1918. Control of even a vicious airborne epidemic like influenza
should not be above our technical capability. Tens or even hundreds
of millions of lives might be at stake over such elementary matters.

The introduction of a new hemolysin into existing anthrax strains in
a demonstration of their pathogenicity in golden hamsters[4]required
additional epitopes to vaccinate those hamsters against this anthrax.
This first example of an artificially contrived new human pathogen
illustrates additional challenges in the fight against emerging
infections.

Natural infection and disease are enough of a challenge and should
not be compounded by human-made agents of death. Biological warfare
cannot be endured and must not be tolerated.

Dr. Lederberg, Nobel laureate in physiology or medicine, is a
research geneticist, Sackler Foundation scholar, and president
emeritus at the Rockefeller University. Dr. Lederberg currently
conducts research on genetic exchange mechanisms in bacteria.

References

1 Lederberg J. Infectious disease as an evolutionary paradigm.
Emerg Infect Dis 1997;3:417-23.
2 Causette M, Planche H, Delepine S, Monsan P, Gaunand A., Lindet
B. The self catalytic enzyme inactivation induced by solvent
stirring: a new example of protein conformational change
induction. Protein Eng 1997;10:1235-40.
3 Kapurniotu A, Bernhagen J, Greenfield N, Al-Abed Y, Teichberg S,
Frank RW, et al. Contribution of advanced glycosylation to the
amyloidogenicity of islet amyloid polypeptide. Eur J Biochem
1998;251:208-16.
4 Pomerantsev AP, Staritsin NA, Mockov YV, Marinin LI. Expression
of cereolysine AB genes in Bacillus anthracis vaccine strain
ensures protection against experimental hemolytic anthrax
infection. Vaccine 1997;15(17-18):1846-50.

They if i can actually make sense out of it,, thats another story that you have heards before.