Mills et al. into host animals during feeding (Gage and Kosoy 2005; Jarrett et al. 2004). Survival of Y. pestis also is influenced by temperature with many fleas clearing infection as temperatures increase above 28°C (Gage and Kosoy 2005; Hinnebusch et al. 1998). Recurrence of viral replication (recrudes- cence) under stress, including heat stress, has been documented for human viral diseases (Halford et al. 1996; Mehta et al. 2004) and is likely to occur within zoonotic host popula- tions also. Replication and shedding of Sin Nombre virus (Table 1) are detected inter- mittently in infected North American deer mice (Botten et al. 2003; Kuenzi et al. 2005). Although mechanisms for the reactivation of viral replication are poorly understood, stress-related immunosuppression has been suggested (Botten et al. 2002; Kuenzi et al. 2005). The relationship between stress and pathogen transmission, replication, persis- tence, and shedding in hosts and vectors is poorly studied. A clearer understanding of this relationship would lead to more accurate predictions of the effects of climate change on VBZD risk to humans. Interactions among climate variables. The amplitude and even the direction of effects of climate on host and vector populations are locally variable and depend upon interactions with other variables (Mills 2005). Contrary to what was observed in New Mexico, the 1997 ENSO did not lead to a net increase in North American deer mouse populations at a high-altitude site in Colorado. Increases in abundance of North American deer mice in Colorado from 1995 to 2000 were associated with increased rainfall during warm periods, but populations crashed after increased rain- fall during cold periods (Calisher et al. 2005). Similarly, the combined effects of temperature and humidity affect the behavior, survival, and reproduction of many vector species. Survival of ticks and fleas are negatively affected by the combination of hot and dry conditions (Gage and Kosoy 2005; Randolph 2004). The same conditions limit the ability of ticks to quest for hosts in exposed environments. These examples indicate that host responses to climate change are multifactorial and their quantitative prediction must consider mul- tiple variables simultaneously, including tem- perature, precipitation, altitude, and location. The separation and independent measurement of these interacting effects have been identi- fied as a research priority (Harvell et al. 2002). Nevertheless, because these factors contribute to overall effects interactively and often operate synergistically, predictions using single variables must be subject to cautious interpretation. Interactions of climate change with anthro- pogenic factors. Just as the interaction effects between various aspects of climate change (e.g., temperature and precipitation) must 1510 be considered to accurately predict the influ- ence of climate on VBZDs, so too must the interactions between climate change and other anthropogenic and natural factors. Human activities facilitate host or vector range shifts by transporting hosts or vectors to new geo- graphic areas (Benedict et al. 2007), including new continents, as was the case with vectors of plague (Parmenter et al. 1999) and West Nile virus (Komar 2003) and hosts of monkey- pox in the United States (Likos et al. 2005). Human migrations in response to climate change may make them more vulnerable to some VBZDs. For example, increases in leish- maniasis were associated with drought-related clustering of humans near water supplies where sand fly vectors were concentrated (Thompson et al. 2002). Human cultural and behavioral differences will alter the end effect of all of the mechanisms discussed above. Although Aedes aegypti, the primary vector of Dengue virus, is likely to achieve northward range expansions in the United States as winter temperatures become warmer, this may not result in dengue epidemics in the United States. In southern Texas, where Ae. aegypti is already established, dengue has remained rare despite epidemics on the Mexican side of the border. This is thought to be due to human-related factors, such as the greater use of air conditioning in the United States, which decreases exposure to mosquitoes (Reiter et al. 2003). Finally, the degree of human intervention to prevent or mitigate adverse effects of climate change on health will affect the eventual outcomes of all of the mechanisms discussed above. This is a large field of study (Confalonieri et al. 2007) but is outside the scope of our discussion. Anthropogenic disturbance of ecosystems will modify the response of many species to climate change. As mentioned, the distribu- tional range of many wildlife species and vec- tors is predicted to shift poleward and toward higher altitudes as the climate warms, perhaps bringing hosts, vectors, and diseases currently restricted to the tropics within the range of temperate population centers. Similar species migrations occurred at the transition from the last ice age to the current interglacial period (Wright et al. 1993). Nevertheless, not all spe- cies and populations will have the option of moving. Nonvolant species on mountain tops or other habitat islands will have nowhere to go. Similarly, isolated foci of some vector- borne diseases that rely on the continued presence of certain hosts and vectors could disappear if movement of either is restricted. Although climate change might result in suit- able climatic conditions elsewhere, these areas will remain disease-free unless all components of the system (host, vector, pathogen) reach and occur simultaneously in these sites for sufficient time to establish transmission cycles. Anthropogenic habitat fragmentation as a result of deforestation, agriculture, road build- ing, construction of towns and cities, and other land use changes will impede migration, jeopardizing the existence of some popula- tions and species (Root and Schneider 2002). A mathematical model was used to predict that > 400 (relatively mobile) bird species will suffer > 50% range contractions and > 50 spe- cies will become extinct because of combined effects of climate change and anthropogenic habitat loss (Jetz et al. 2007). According to the IPCC’s Fourth Assessment Report, 20–30% of plant and animal species are likely to be at increasingly high risk of extinction as global mean temperatures exceed 2–3°C above pre- industrial levels (Fischlin et al. 2007). It seems intuitive that extinctions result- ing in fewer species of host animals should decrease the number of potential zoonotic pathogens and thus the incidence of VBZDs. Several scientists have suggested that high biodiversity is causally related to high lev- els of infectious disease, both locally and regionally (Sattenspiel 2000; Wolfe et al. 2005). Indeed, some highly specific patho- gens are likely to disappear with their hosts. Nevertheless, extinction and biodiversity loss may have some counterintuitive affects on the incidence of some VBZDs. Extinctions will occur selectively with habitat and dietary spe- cialists being affected first (MacDonald and Brown 1992; Warren et al. 2001). Meanwhile more opportunistic, generalist species may not only survive but thrive in the absence of competition from specialists. In their study of climate change and altitudinal migration in Yosemite National Park, Moritz et al. (2008) found that opportunistic small mammal spe- cies (those that were short-lived and had more litters per year) were more likely to expand their range upward than were their long-lived, less fecund counterparts. The host species for most of the known rodent-borne hemor- rhagic fever viruses that affect humans are opportunistic species (Mills 2006). Although it is possible that this pattern is due, at least in part, to sampling error (diseases associ- ated with anthropophilic species would be the first to come to our attention), the pattern could be the logical consequence of several characteristics of opportunistic species (high vagility, rapid growth, early reproduction, high fecundity, and capacity to sustain high population densities that are conducive to the transmission of pathogens) that would facilitate the evolution and maintenance of pathogens. Further, decreases in the species diversity of potential host assemblages have been associated with increased prevalence of infection by zoonotic pathogens in host popu- lations both for vector-borne diseases (Ostfeld and Keesing 2000) and for nonvector-borne zoonoses (Mills 2005). Thus, selective extinc- tions associated with climate change can result ovlume 118 | number 11 | November 2010 • Environmental Health Perspectives