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6 Genetic Mechanisms Governing Resistance or Susceptibility to Infectious Diseases Specific immunity has been associated with protection against most fortes of infectious agents in rodents and other vertebrate animals. The role of MHC genes in this specific immunity has received much attention. It is the subject of many review articles (Benacerraf and Rock, 1984; David, 1984; Zink- ernagel et al., 1985; Ashman, 1987; Van Bleek et al., 1988) and will not be discussed in this section. Likewise, a review of the molecular genetics of retroviruses (oncornaviruses), which has been addressed elsewhere in great detail, is beyond the scope of this report. Those interested in learning more about the genetic regulation and expression of retroviruses are urged to read any of a number of current reviews on the subject (Pincus, 1980; Kulstad, 1986; Salzman, 19861. This chapter deals with susceptibility and resistance to infectious agents not associated with specific immunity or linked to the MHC. The resistance of a host to an infectious agent is controlled by several nonspecific factors, including age, gender, diet, heredity, hormone status, metabolic changes, macrophage function, and the inhibitory substances in- terferon and thymosin. In addition, resistance or susceptibility is relative to and dependent on strain, dose, and route of inoculation of the infectious agent. Various strains of mice are known to differ in their susceptibilities to naturally occurring viral agents such as Sendai, ectromelia, polyoma, and lactic dehydrogenase viruses (Bang and Warwick, 1960; Chang and Hilde- mann, 1964; Kees and Blanden, 1976; Martinez et al., 19801. Strain dif- ferences are also observed in their susceptibilities to such experimental virus infections as herpes simplex type 1, influenza A, measles, and flaviviruses 161
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162 IMMUNODEFICIENT RODENTS (Sabin, 1952; Lindemann, 1964; Lopez, 1975; In each of these instances, genes outside the MHC appear to be important determinants of susceptibility. A single autosomal dominant trait not linked to H-2 (actually it is found on chromosome 1) confers resistance to Sendai virus infection in C57BL/6J mice (Brownstein, 19831. Both H-2 and non- H-2 loci have been found to confer resistance to the mouse coronavirus MHV3, and it has been postulated that the genes conferring this resistance operate through macrophages and cells that mount an immune response (Du- puy et al., 19841. The resistance of C57BL/6 mice to the demyelinating disease caused by the JHM strain of MHV has been shown to be dependent on T-cell activity and not interferon (Sorensen et al., 19821; however, it is also greatly influenced by the age of the host (Picker et al., 19811. In rats, a demyelinating disease associated with autoimmunity can be induced by the JHM strain of MHV. Intracerebral infection of LEW rats can lead to encephalomyelitis (Nagashima et al., 19791. BN rats do not develop the disease; a strong, local, virus-specific antibody response effectively con- trols the intracerebral spread of JHM virus (Dorries et al., 19871. The de- myelinating disease is largely caused by a T-cell-mediated delayed-type hypersensitivity reaction against brain tissue. Adoptive transfer from diseased LEW rats of lymphocytes restimulated in vitro with basic myelin protein leads to lesions resembling an experimental allergic encephalomyelitis in recipients (Watanabe et al., 19831. Host factors such as strain and age affect the development of the disease (Wege et al., 19871. A gene outside the MHC (RT1) appears to control suceptibility or resis- tance. Preliminary data map this gene into linkage group V of the rat (H. J. Hedrich, Central Institute for Laboratory Animal Breeding, Hannover, Fed- eral Republic of Germany, unpublished data). Ectromelia virus (mousepox) has been extensively studied in various inbred strains of mice. When inoc- ulated into the footpad, marked differences in the 50 percent lethal dose (LDso) have been observed among strains, with C57BL mice being the most resistant (O'Neill and Blanden, 19831. Both H-2 and non-H-2 genes appear to be responsible for this resistance, and studies in chimeric mice have demonstrated that the superior resistance of C57BL/6 over BALB/c mice operates through reduced early (1-2 days' virus transmission to the lym- phoreticular system by a radioresistant cell or substance. Noteworthy is the report of Wallace and Buller (1985) that a strain of ectromelia virus isolated in 1979 from an outbreak at the National Institutes of Health could be pas- saged up to seven times by exposure to infected C57BL/6J cage mates without any apparent clinical illness. Furthermore, these authors found that females are significantly more resistant than males. These studies are in marked contrast to earlier ones in which the Moscow strain of ectromelia virus was used. Outbred stocks of mice were exquisitely sensitive to this strain of the virus, and the virus was invariably fatal (Fenner, 19491. Rager-Zisman et al ., 19801.
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GENETIC MECHANISMS 163 The X-linked resistance of mice to high doses of herpes simplex virus type 2 has been found to correlate with interferon production (Pedersen et al., 1983~. By contrast, the increased susceptibility of male mice to inocu- lation with herpes simplex virus type 1 is thought to involve antibody-depressing mechanisms of androgen-sensitive cell populations (Knoblich et al., 19831. BALB/c mice carry genes that impart protection against lethal encephal- omyocarditis virus infection by influencing the action of interferon (Dandoy et al., 19821. In C3H/RV mice, however, an autosomal dominant gene confers resistance to flavivirus infection that is independent of interferon action (Brinton et al., 19821. Differential susceptibility to the demyelinating disease associated with Theiler's murine encephalomyelitis virus is controlled by at least two non-H-2 genes in mice (Melvold et al., 19871. Strain dif- ferences in susceptibility to viral agents have also been described in rats (Sorensen et al., 1982), hamsters (Fultz et al., 1981), and guinea pigs (Jahr- ling et al., 19821. The severity of pulmonary lesions in mice and rats inoculated intranasally with Mycoplasma pulmonis has been studied (Cassell, 19821. Saito et al. (1978b) found that ddY (not standardized nomenclature) mice are less re- sistant to respiratory disease than are ICR mice. Likewise, LEW rats are more susceptible to severe pulmonary disease caused by M. pulmonis than are F344 rats when age, sex, and environmental factors are controlled (Davis et al., 19821. In addition, the infection persists in LEW rats for 120 days, as opposed to 28 days in F344 rats. It has been suggested that M. pulmonis is a B-cell activator in LEW rats, and differences in the severity of infection can be attributed to differences in nonspecific lymphocyte activation (Naot et al., 19791. Resistance and susceptibility to other infectious and parasitic agents have also been examined. Jerrells and Osterman (1982) found that resistance to intraperitoneal infection with Rickettsia tsutsugamushi in C3H/RV mice was not radiation sensitive and most likely concerned differences in Ia-positive macrophages (Jerrells, 19831. Similarly, the resistance of mice to infection with Rickettsia akari was found to reside in macrophages and was determined by loci other than Lps~ (Nacy and Meltzer, 19821. Morozumi and others (1981) found that the susceptibility of inbred strains of mice to Blastomyces dermatitidis was not related to cellular or humoral immunity but rather to macrophage activity controlled by a non-Lps locus. Likewise, Kirkland and Fierer (1983) found that murine resistance to Coc- cidioides immitis is controlled as a dominant trait and is not associated with the Lsh or Lps loci or with the genes controlling resistance to Blastomyces dermatitidis. Murine resistance to paracoccidioidomycosis was found to be controlled by the autosomal dominant gene Pbr, which is not linked to Cms, the resistance gene for coccidioidomycosis (Calich et al., 19871. R. G. Bell and colleagues (1984) discovered that the rapid expulsion of
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164 IMMUNODEFICIENT RODENTS Trichinella spiralis in mice is controlled by an autosomal dominant gene called Ihe-1 (intestinal helminth expulsion-1), which is not linked to the MHC, Lsh, or chromosome 7. This gene, Ihe-l, was not linked to genes controlling resistance to Taenia teaniaformis, Giardia muris, Trichuris muris, or Nematospiroides dubius. Although the mechanisms controlling resistance and susceptibility to the agents listed above are, for the most part, undefined, it is known that they do not involve specific immunity. As additional loci are identified that control various aspects of the immune response, some of these resistance genes might be found to have a basis in specific immunity.