Abstract
Various respiratory viral infections in general and seasonal influenza in particular may increase the susceptibility to bacterial infections. Plague caused by Yersinia pestis endangers large populations during outbreaks or bioterrorism attacks. Recommended antibiotic countermeasures include well-established protocols based on animal studies and corroborated by effective treatment of human cases. Until now, prior exposure to viral respiratory infections was not taken into consideration when selecting the appropriate treatment for plague. Here, we show that as late as 25 days after exposure to influenza virus, convalescent mice still exhibited an increased susceptibility to sublethal doses of Y. pestis, presented with aberrant cytokine expression, and impaired neutrophil infiltration in the lungs. Increased levels of M2 alveolar macrophages and type II epithelial cells, as well as induction in metalloproteases expression and collagen and laminin degradation, suggested that the previous viral infection was under resolution, correlating with enhanced susceptibility to plague. Surprisingly, postexposure prophylaxis treatment with the recommended drugs revealed that ciprofloxacin was superior to doxycycline in mice recovering from influenza infection. These results suggest that after an influenza infection, the consequences, such as impaired immunity and lung tissue remodeling and damage, should be considered when treating subsequent Y. pestis exposure.
Highlights
S. aureus, H. influenza and o thers[9,11,12]
The data support the notion that the absence of an adequate inflammatory response concomitant with substandard neutrophil infiltration and bacterial clearance in the lungs was associated with a resolution and tissue remodeling processes; this phenomenon was depicted by an elevation in the number of alveolar macrophages (AMs) harboring the M2 phenotype, the induction of matrix metalloprotease (MMP) expression and extracellular matrix (ECM) remodeling and the elevation in type 2 epithelial cells near the damaged alveolus
Mice challenged at 25 dpii had an initial higher cytokines and chemokines levels as compare to naïve mice, these levels were not increased after Y. pestis infection, correlating with their high susceptibility
Summary
S. aureus, H. influenza and o thers[9,11,12]. Recently, an association between severe influenza of immunocompetent patients and invasive Aspergillus infection of the lungs has been reported, emphasizing the risk of secondary opportunistic infections with influenza[13] Reports indicate that bacterial coinfections are found in 4–30% of adults and in 22–33% of children who are hospitalized with community-acquired viral pneumonia[14], and up to 75% of those infected with influenza and develop pneumonia are confirmed to have a bacterial c oinfection[11]. The data support the notion that the absence of an adequate inflammatory response concomitant with substandard neutrophil infiltration and bacterial clearance in the lungs was associated with a resolution and tissue remodeling processes; this phenomenon was depicted by an elevation in the number of alveolar macrophages (AMs) harboring the M2 phenotype, the induction of matrix metalloprotease (MMP) expression and extracellular matrix (ECM) remodeling and the elevation in type 2 epithelial cells near the damaged alveolus This ongoing process and the consequent inferior immune response have an important impact on treatment with the CDC-recommended antibiotic doxycycline (Doxy), but not ciprofloxacin (Cipro), against pulmonary Y. pestis infection during late-stage postinfluenza
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