Pneumovirus-Induced Lung Disease in Mice Is Independent of Neutrophil-Driven Inflammation

Abstract

The human pneumovirus respiratory syncytial virus (RSV) is the most common pathogen causing lower respiratory tract disease in young children worldwide. A hallmark of severe human RSV infection is the strong neutrophil recruitment to the airways and lungs. Massive neutrophil activation has been proven detrimental in numerous diseases, yet in RSV the contribution of neutrophils to disease severity, and thereby, the relevance of targeting them, is largely unknown. To determine the relevance of potential neutrophil targeting therapies, we implemented antibody-mediated neutrophil depletion in a mouse pneumonia virus of mice (PVM) model. PVM is a host specific murine pneumovirus closely related to human RSV, which reproduces many of the features of RSV infection, such as high viral replication and neutrophil recruitment. Clinical disease and markers of lung inflammation and injury were studied in PVM-infected mice treated with either depleting or isotype control antibodies. To confirm our results we performed all experiments in two mice strains: C57Bl6 and BALBc mice. Neutrophil depletion in blood and lungs was efficient throughout the disease. Remarkably, in both mouse strains we found no difference in clinical disease severity between neutrophil-depleted and control arms. In line with this observation, we found no differences between groups in histopathological lung injury and lung viral loads. In conclusion, our study shows that in mice neutrophil recruitment to the lungs does not affect disease outcome or viral clearance during severe PVM infection. As such, this model does not support the notion that neutrophils play a key role in mouse pneumovirus disease.

Gr-1+ Cells Other Than Ly6G+ Neutrophils Limit Virus Replication and Promote Myocardial Inflammation and Fibrosis Following Coxsackievirus B3 Infection of Mice

“…Mice depleted of Gr-1 cells exhibited a robust expansion of circulating Ly-6G+ neutrophils (Figure 2B ), but were nonetheless highly susceptible to CVB3, also indicating that peripheral neutrophils are insufficient for host defense against CVB3. In accordance with our data, recent studies indicate that lung-recruited neutrophils have no effect on pneumonia virus of mice (PMV) replication or histopathological lung injury (Cortjens et al, 2016 ). Robust Th17-induced airway neutrophils are unable to control mouse adenovirus type 1 (MAV-1) infection or virus-induced pulmonary inflammation (McCarthy et al, 2014 ).…”

“…The requirement for neutrophils in host defense to bacterial and fungal infections is well described (Huppler et al, 2014 ). However, role of neutrophils in host defense to viral infections remains poorly characterized (Cortjens et al, 2016 ). Abundant neutrophil infiltration (up to 80% of infiltrated leucocytes) has been detected in the airways and lungs during human respiratory syncytial virus (RSV) (Geerdink et al, 2015 ) and herpes simplex virus (HSV) infections (Stock et al, 2014 ).…”

Platelet glycoprotein VI aids in local immunity during pneumonia-derived sepsis caused by gram-negative bacteria

“…11,12 We therefore assessed whether lung bleeding occurred in GPVI-or CLEC2-depleted mice during Klebsiella pneumosepsis. In these studies, some groups were treated with either the platelet-depleting antibody anti-GPIb-a and/or the neutrophil-depleting antibody anti-Gr1, which in accordance with earlier reports reduced platelet counts to ,1% 13 and neutrophil counts to ,10% 33 of normal level, respectively. Consistent with previous findings, 13 control mice did not shown bleeding in the lungs, whereas thrombocytopenic mice demonstrated pulmonary hemorrhage 12 hours after infection and to a larger extent at 36 hours, as assessed macroscopically, on hematoxylin and eosin-stained lung sections and by lung hemoglobin levels (Figure 6A-F).…”

Human neutrophils are not activated by Zika virus but reduce the infection of susceptible cells

“…In this scenario, we did not observe a direct action of neutrophils in preventing ZIKV spread to the lymph nodes in the first hour after ZIKV inoculation in a setting where an inflammatory environment had been previously induced by LPS injection. Interestingly, other authors reported that besides an extensive neutrophil recruitment to the inflammation site after certain virus infections (RSV, Herpes simplex virus type 1 and Coxsackievirus B3), neutrophils did not play an important role in viral replication and disease susceptibility, which in turn was exerted by monocytes and macrophages (71)(72)(73)(74).…”