Pulmonary insults exacerbate susceptibility to oral Listeria monocytogenes infection through the production of IL-10 by NK cells

Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host's ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including Natural Killer (NK) cells. Lastly, the ability of Ncr1+ derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa. Author summary The bacterial pathogen Listeria monocytogenes (Lm) causes food-borne infections in humans and animals. Most humans who consume Lm-contaminated foods develop mild symptoms, but in a subset of individuals Lm causes severe systemic infections that are often lethal. Although the factors that predispose individuals to develop severe Lm infection are not well understood, systemic infections require bacteria to disseminate from the intestines to the bloodstream and peripheral tissues. Here we show in a murine model of infection that feeding of Lm alone results in the dissemination of only small numbers of bacteria that are contained and fail to cause symptoms. However, feeding of Lm in mice that also encounter a second infection in the lungs, or have exposure to microbial products in the lungs, results in a severe infection with large number