Ongoing research focuses on the exploration of pathologic inflammatory responses to acute respiratory virus infection and the use of this information to develop creative strategies to circumvent these lethal sequelae characteristic of this disease. Our first original research publication features our ongoing interest in the immunomodulatory properties of Lactobacillus at the respiratory mucosa and protection against acute respiratory virus infection. We reported previously that priming of the respiratory tract with immunobiotic Lactobacillus prior to virus challenge protects mice against subsequent lethal infection with pneumonia virus of mice (PVM). We present here the results of gene microarray which document differential expression of proinflammatory mediators in response to PVM infection alone and those suppressed in response to Lactobacillus plantarum. We also demonstrate for the first time that intranasal inoculation with live or heat-inactivated L. plantarum or Lactobacillus reuteri promotes full survival from PVM infection when administered within 24h after virus challenge. Survival in response to L. plantarum administered after virus challenge is associated with suppression of proinflammatory cytokines, limited virus recovery, and diminished neutrophil recruitment to lung tissue and airways. Utilizing this novel post-virus challenge protocol, we found that protective responses elicited by L. plantarum at the respiratory tract were distinct from those at the gastrointestinal mucosa, as mice devoid of the anti-inflammatory cytokine, interleukin (IL)-10, exhibit survival and inflammatory responses that are indistinguishable from those of their wild-type counterparts. Finally, although L. plantarum interacts specifically with pattern recognition receptors TLR2 and NOD2, the respective gene-deleted mice were fully protected against lethal PVM infection by L. plantarum administration, as are mice devoid of type I interferon receptors. Taken together, L. plantarum is a versatile and flexible agent that is capable of averting the lethal sequelae of severe respiratory infection both prior to and post-virus challenge via complex and potentially redundant mechanisms (Percopo et al., 2015, Antiviral Res. 121, 109-119). As part of our long-term collaboration with the laboratory of Dr. Paul Foster, we contributed to an original research study of the systemic impact of PVM infection. In this study, we determined that, even if virus replication is limited to the lung tissue, the impact of the infection itself could be broad-reaching and systemic. In this specific study, we assessed the impact of acute pneumovirus infection in C57BL/6 mice on hematopoiesis taking place in the bone marrow. We hypothesized that inflammatory cytokine production in the lung upregulates myeloid cell production in response to infection. Specifically, we demonstrated a dramatic increase in the percentages of circulating myeloid cells in association with pronounced elevations in inflammatory cytokines in serum, bone, and lung tissue. Increased percentages of hematopoietic stem cells were detected, accompanied by an increase in the proportions of committed myeloid progenitors, as determined by colony-forming unit assays. However, no functional changes in hematopoietic stem cells occurred, as assessed by competitive bone marrow reconstitution. Systemic administration of neutralizing Abs to either TNF-alpha; or IFN-gamma; blocked expansion of myeloid progenitors in the bone marrow and also limited virus clearance from the lung. These findings suggest that acute inflammatory cytokines drive production and differentiation of myeloid cells in the bone marrow by inducing differentiation of committed myeloid progenitors. Our findings provide insight into the mechanisms via which innate immune responses regulate myeloid cell progenitor numbers in response to acute respiratory virus infection (Maltby et al., 2014, J. Immunol. 193:4072-4082).
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