There is ample evidence of the evolution of differential susceptibility to major infectious diseases (Vogel and Motulsky 1997; Ewald 2004). The best-known examples are two different types of malaria, due to Plasmodium falciparum and to Plasmodium vivax.
The protozoan parasite P. falciparum causes the most severe form of malaria, with more than one million deaths annually worldwide. Rates of malaria infection are correlated with the distribution of the obligate intermediate host, Anopheles mosquitoes that multiply in stagnant water, a situation driven by agricultural practices involving deforestation both historically and currently. The most obvious ways to avoid malaria infection are migration away from geographic areas with high prevalence of Anopheles and Plasmodium and elimination of the host with antimalarial chemicals such a dichlorodiphenyl–trichloroethane (DOT), which was very effective globally before its ban because of adverse effects on bird populations. Malaria also is an outstanding example of ecogenetics, the interaction of environmental exposures with inherited susceptibility. Children and adults with hemoglobin S (sickle cell trait) have red blood cells less hospitable to the life stage of the malaria parasite that infects and propagates in the blood, compared with the red blood cells of individuals with normal HbA. HbS individuals are more likely to survive the infection and go on to reproduce, transmitting their genes to the next generations. This is natural selection in action. Allison (1954) deduced that malaria was the selective factor maintaining the HbS gene in populations in the face of high mortality from sickle cell anemia when individuals received a double dose of the gene (HbSS). HbC, HbE, beta thalassemias, and glucose-6-phosphate dehydrogenase deficiencies fit this same pattern of “balanced polymorphisms” (Motulsky 1964). A 20% increase in fitness for individuals with the trait could balance an 85% decrease in fitness of homozygous HbSS individuals (Gelehrter et al. 1998).
Phylogenetic analyses have radically revised our thinking about the origin of P. falciparum. For many years, the evidence seemed to point to co-speciation of P. falciparum in humans and Plasmodium reichenowi in chimpanzees, evolved separately from a presumed common ancestor over 5–7 Ma. That was based on a single isolate of P. reichenowi. Rich et al. (2009), with eight new isolates, showed that the global totality of P. falciparum strains is included within the much more diverse P. reichenowi variation. All extant P. falciparum populations seem to have originated from the parasite infecting chimpanzees by a single-host transfer about 10,000 years ago. Moreover, inactivation of the gene CMAH in the human lineage blocked conversion of the sialic acid N-acetylneuraminic acid (5Ac) to N-glycolylneuraminic acid (Neu5Gc), making humans resistant to P. reichenowi.
Vivax malaria represents an entirely different mechanism for evolution of resistance and susceptibility. International studies of blood group antigens on red blood cells revealed that West African populations had a Duffy-negative phenotype and Fy-/Fy- genotype, which are rare among Caucasian and Asian populations. Fy-/Fy- individuals are completely resistant to P. vivax infection because the Fy blood group antigen is the receptor through which the P. vivax parasite enters erythrocytes. Whether this infection is sufficiently life-threatening to fully account for the ubiquitous presence of Fy- in these populations is not resolved (Vogel and Motulsky 1997; Omenn 2010).
The Duffy mechanism was a clue to explain the epidemiological observation that some men very highly exposed to the HIV/AIDS virus did not become infected. The most striking specific mechanism involves a mutant CCR5 receptor on lymphocytes (a 32 amino acid deletion). CCR5 is an essential component of the entry mechanism for HIV; if there is no entry, there is no infection and there is no risk of transmission to others. We have no clue as to the natural selection driver for CCR5 mutations to accumulate in the human population (Heeney et al. 2006). We now know 20 polymorphisms of receptors, co-receptors, cytokine ligands, and HLA genes that influence susceptibility to HIV infection, replication, or relevant innate or adaptive immunity (Heeney et al. 2006). Viruses have a long history of co-evolution with molecules of the immune system. The presence of the CCR5 receptor seems to protect against West Nile virus; thus, we should be alert that development and public health use of inhibitors of CCR5 to reduce risk of HIV/AIDS could lead to increased risk of West Nile virus-induced encephalitis. Since the emergence of HIV/AIDS in the early 1980s, public interest in the origins of the HIV viruses has been intense; there is now strong evidence that HIV-1 and HIV-2 evolved from chimpanzees and from sooty mangabeys, respectively. Also, the human genome has a large array of endogenous retroviral sequences, suggesting a long history of co-evolution with retroviruses.
SARS and Influenza
The coronavirus epidemic Severe Acute Respiratory Syndrome (SARS) appeared in southeast China and Hong Kong in 2002 and suddenly spread to Toronto via an air traveler. Modern molecular genetic epidemiologic methods swiftly identified the virus and permitted surveillance and control of this epidemic. The key link was humans handling infected animals. Global surveillance of highly exposed animal handlers is a strategy to identify such “emerging infections” at an early stage (Wolfe et al. 1998).
The best known viral infection linked through animal hosts is influenza. Influenza viruses are highly mutable and capable of rapid adaptation to selective factors in their environment, including vaccines. The H5N1 (“avian”) and H1N1 (“swine”) have quite different origins, with reassortment of strains in their animal hosts. One major barrier limiting cross-species transmission into humans (and vice versa) is the evolution of differences in sialic acid linkage binding specificity between humans and birds and humans and primates (Rich et al. 2009). Current research uses reconstituted influenza strains and reverse genetics to seek the specific genes and gene combinations that may drive virulence and host range; other researchers model the effects of vaccines and drugs on evolution and dynamics of the flu strains.
Modern genomic analyses of bacteria DNA from organisms that are not readily cultured and grown in the laboratory have revealed remarkable co-existence of microbes in every ecosystem, including all the internal and external surfaces of our bodies. These complex microbial communities are called the “microbiome”. There are an estimated ten times as many microbial cells as human cells in our bodies. They perform critical functions in digestion and host defenses. We provide unique habitats that have restricted colonization to a relatively small range of micro-organisms. Our changing hygiene practices, diet, medical therapies, chemical exposures, and public health programs continue to cause changes in the microbiome (Turnbaugh et al. 2007).
Antibiotic Resistance/Evolution in Action
Within the microbial world, there is interspecies competition and cooperation mediated through exchange of genetic material. Microbes compete for food and space, adapting to selective pressures. Fungi are particularly notable for evolution of antimicrobial chemical products that protect them against bacteria. Patients have benefitted from these antibiotics found in nature, starting with Fleming’s use of an extract of Penicillium to kill Gram-positive bacteria. Microbes respond promptly to negative natural selection in the form of antibiotics by developing genetically transmitted resistance to the action of individual antibiotics or sets of antibiotics. Strains of Mycobacterium tuberculosis resistant to multiple drugs put healthcare workers at great risk; when these strains were recognized about 20 years ago, an aggressive public health campaign to identify and isolate such patients and ensure full dosage therapy with whatever agents still were effective contained the outbreaks. A similar challenge exists today with multiply resistant Staphylococcal aureus, acquired mostly in hospitals but increasingly in the community. Individuals immune-suppressed due to HIV infection, steroid treatments, cancer chemotherapy, or genetic immune deficiency disorders are particularly vulnerable to a broad range of infectious agents.
Vaccination has been a spectacularly effective public health intervention over the past 230 years. Modern vaccination approaches can be designed, in at least some situations, to select for less rather than more virulent strains or for other desired characteristics. For example, the diphtheria toxoid vaccine selects against toxin production, which is what causes disease, rather than against growth or survival of the Corynebacterium. Vaccination with the seven-conjugate vaccine against Streptococcus pneumonia has reduced carriage of penicillin-resistant serotypes but not invasive isolates (Karnezis et al. 2009). Bioinformatics tools, databases, and ontologies are helping researchers to organize information about immunization and to design new vaccination strategies (www.violinet.org/vaccineontology).