Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens

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Abstract
Most inbred mice carry germline proviruses of the retrovirus, mouse mammary tumor virus (MMTV) (called Mtvs), which have multiple replication defects. A BALB/c congenic mouse strain lacking all endogenous Mtvs (Mtv-null) was resistant to MMTV oral and intraperitoneal infection and tumorigenesis compared to wild-type BALB/c mice. Infection of Mtv-null mice with an MMTV-related retrovirus, type B leukemogenic virus, also resulted in severely reduced viral loads and failure to induce T-cell lymphomas, indicating that resistance is not dependent on expression of a superantigen (Sag) encoded by exogenous MMTV. Resistance to MMTV in Mtv-null animals was not due to neutralizing antibodies. Further, Mtv-null mice were resistant to rapid mortality induced by intragastric inoculation of the Gram-negative bacterium, Vibrio cholerae, but susceptibility to Salmonella typhimurium was not significantly different from BALB/c mice. Susceptibility to both MMTV and V. cholerae was reconstituted by the presence of any one of three endogenous Mtvs located on different chromosomes and was associated with increased pathogen load. One of these endogenous proviruses is known to encode only Sag. Therefore, Mtv-encoded Sag appears to provide a unique genetic susceptibility to specific viruses and bacteria. Since human endogenous retroviruses also encode Sags, these studies have broad implications for pathogen-induced responses in mice and humans. Mouse mammary tumor virus (MMTV) is a retrovirus that causes breast cancer in mice. MMTV-induced breast cancers represent a well-established model for human breast cancer research. Mice become infected by virus particles in mother's milk (exogenous MMTV), and insertion of exogenous MMTV into somatic cell DNA sporadically leads to genetic damage and cancer. Alternatively, if exogenous MMTVs infect germline cells, the viral genome becomes a stable part of the mouse genome and may be inherited from either parent (endogenous MMTV). In this report, the authors demonstrate that mice carrying endogenous MMTV in their genomes are more susceptible to disparate infectious agents, such as exogenous MMTV and the cholera-producing bacteria, Vibrio cholerae. However, this effect was selective since disease induced by another related bacteria, Salmonella typhimurium, was not affected. Genetic evidence suggests that a viral protein produced by endogenous MMTVs enhances pathogen-induced disease and death. Further, the human genome contains many human endogenous virus type Ks, which highly resemble MMTVs and also may influence disease. Therefore, this study suggests that endogenous retroviruses found in the mouse and human genomes alter the course of disease induced by multiple pathogenic organisms.