RESUMO
Aspergillus fumigatus is an environmental fungus that can cause invasive pulmonary aspergillosis when spores are inhaled into the respiratory tract and invade airway or lung tissue. Influenza is a common respiratory virus that can cause severe respiratory disease, and postinfluenza invasive pulmonary aspergillosis, which is becoming a well-recognized clinical problem, typically occurs in critically ill patients. Mice challenged with influenza A PR/8/34 H1N1 and subsequently challenged with A. fumigatus had increased fungal burden, viral burden, inflammation, and mortality compared with single infected mice. Neutrophil recruitment in the lung of superinfected mice was decreased; however, mice were not neutropenic, and there was no difference in absolute blood neutrophils between groups. Additionally, CXCL1 and CXCL2 were decreased in lungs of superinfected mice compared with controls. IFN levels were increased in mice that received influenza, and deletion of STAT1 resulted in decreased fungal burden, increased airway and lung neutrophils, and increased CXCL1 compared with wild-type mice, whereas deletion of STAT2 did not change fungal burden or airway neutrophilia compared with wild-type mice. These data demonstrate a mechanism by which influenza A-induced STAT1 signaling inhibits neutrophil recruitment and increases susceptibility to postinfluenza invasive pulmonary aspergillosis.
Assuntos
Aspergillus fumigatus/fisiologia , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/imunologia , Aspergilose Pulmonar Invasiva/imunologia , Pulmão/imunologia , Neutrófilos/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Quimiocina CXCL1/metabolismo , Contagem de Colônia Microbiana , Progressão da Doença , Humanos , Evasão da Resposta Imune , Influenza Humana/complicações , Aspergilose Pulmonar Invasiva/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos , Infecções por Orthomyxoviridae/complicações , Fator de Transcrição STAT1/metabolismo , Transdução de SinaisRESUMO
Postinfluenza bacterial superinfections cause increased morbidity and mortality compared with singular infection with influenza during both pandemics and seasonal epidemics. Vaccines and current treatments provide limited benefit, a rationale to conduct studies utilizing alternative therapies. FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. MEDI4893*, an anti-Staphylococcus aureus α-toxin mAb, has been shown to improve survival when administered prophylactically prior to S. aureus pneumonia. Our objective was to determine if mAbs can improve survival during postinfluenza bacterial pneumonia. We administered FY1 in a murine model of postinfluenza methicillin-resistant S. aureus (MRSA) pneumonia and observed improved survival rates when given early during the course of influenza infection. Our findings indicate decreased lung injury and increased uptake and binding of bacteria by macrophages in the mice that received FY1 earlier in the course of influenza infection, corresponding to decreased bacterial burden. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection.
Assuntos
Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Pneumonia Estafilocócica/tratamento farmacológico , Superinfecção/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/farmacologia , Anticorpos Amplamente Neutralizantes/farmacologia , Anticorpos Amplamente Neutralizantes/uso terapêutico , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/imunologia , Influenza Humana/mortalidade , Influenza Humana/virologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Staphylococcus aureus Resistente à Meticilina/imunologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Pneumonia Estafilocócica/imunologia , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/mortalidade , Superinfecção/imunologia , Superinfecção/microbiologia , Superinfecção/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
Secondary bacterial respiratory infections are commonly associated with both acute and chronic lung injury. Influenza complicated by bacterial pneumonia is an effective model to study host defense during pulmonary superinfection due to its clinical relevance. Multiprotein inflammasomes are responsible for IL-1ß production in response to infection and drive tissue inflammation. In this study, we examined the role of the inflammasome during viral/bacterial superinfection. We demonstrate that ASC-/- mice are protected from bacterial superinfection and produce sufficient quantities of IL-1ß through an apoptosis-associated speck-like protein containing CARD (ASC) inflammasome-independent mechanism. Despite the production of IL-1ß by ASC-/- mice in response to bacterial superinfection, these mice display decreased lung inflammation. A neutrophil elastase inhibitor blocked ASC inflammasome-independent production of IL-1ß and the IL-1 receptor antagonist, anakinra, confirmed that IL-1 remains crucial to the clearance of bacteria during superinfection. Delayed inhibition of NLRP3 during influenza infection by MCC950 decreases bacterial burden during superinfection and leads to decreased inflammatory cytokine production. Collectively, our results demonstrate that ASC augments the clearance of bacteria, but can also contribute to inflammation and mortality. ASC should be considered as a therapeutic target to decrease morbidity and mortality during bacterial superinfection.