Neutrophils are needed for an effective immune response against pulmonary rat coronavirus infection, but also contribute to pathology

Abstract

Polymorphonuclear neutrophils (PMN) infiltrate the respiratory tract early after viral infection and can contribute to both host defence and pathology. Coronaviruses are important causes of respiratory tract infections, ranging from mild to severe depending on the viral strain. This study evaluated the role of PMN during a non-fatal pulmonary coronavirus infection in the natural host. Rat coronavirus (RCoV) causes respiratory disease in adult rats, characterized by an early PMN response, viral replication and inflammatory lesions in the lungs, mild weight loss and effective resolution of infection. To determine their role during RCoV infection, PMN were depleted and the effects on disease progression, viral replication, inflammatory response and lung pathology were analysed. Compared with RCoV infection in control animals, PMN-depleted rats had worsened disease with weight loss, clinical signs, mortality and prolonged pulmonary viral replication. PMNdepleted animals had fewer macrophages and lymphocytes in the respiratory tract, corresponding to lower chemokine levels. Combined with in vitro experiments showing that PMN express cytokines and chemokines in response to RCoV-infected alveolar epithelial cells, these findings support a role for PMN in eliciting an inflammatory response to RCoV infection. Despite their critical role in the protection from severe disease, the presence of PMN was correlated with haemorrhagic lesions, epithelial barrier permeability and cellular inflammation in the lungs. This study demonstrated that while PMN are required for an effective antiviral response, they also contribute to lung pathology during RCoV infection.

Neutrophil-derived chemokines on the road to immunity

“…Finally, rat neutrophils incubated in vitro with conditioned medium from coronavirus (CoV)-infected alveolar epithelial cells have been shown to display higher mRNA levels of CXCL1, CXCL2, CXCL10 and CXCL11, CCL2, CCL4, CCL7, CCL9/mMIP-1␥, CCL12/MCP-5 and CCL22 as compared to neutrophils incubated in a control medium [79]. The potential validity of these in vitro observations in vivo have been confirmed in a rat model of non-fatal lung CoV infection, in which neutrophil-depleted rats displayed fewer macrophages and lymphocytes in their respiratory tract, as compared to nondepleted rats, and lower chemokine levels [79].…”

Anvillea garcinii extract inhibits the oxidative burst of primary human neutrophils

“…Phagocytic cells such as neutrophils play a key role in innate immunity because of their ability to recognize, ingest and destroy pathogens by oxidative and nonoxidative mechanisms. However, neutrophil hyperactivation has been shown to induce tissue injury and inflammatory reactions [1,8]. Thus, inhibition of neutrophil hyper activation represents an interesting strategy to develop novel anti-inflammatory agents.…”

“…Degranulation, a mechanism independent of ROS production, can also be incriminated as being a main cause of pulmonary disorders such as severe asphyxic episodes of asthma [7]. The dual role of neutrophils has been further highlighted during respiratory viral infection whereby it contributed to beneficial antiviral responses as well as detrimental tissue pathology and cellular inflammation [8]. Thus, the inhibition of excessive oxidant production and degranulation represent an important therapeutic target and could in part explain the beneficial effects of certain natural products used against inflammatory disorders.…”

Viral Disease

“…Using an in vitro model system, RCV infection induced proinflammatory cytokines and, specifically, CXC chemokines that inhibit polymorphonuclear leukocyte (PMN) apoptosis in type 1-like alveolar epithelia Rzepka et al, 2012). Furthermore, it was shown that RCV-infected rats deficient in PMNs have more severe and prolonged disease, indicating PMNs are required for an effective antiviral response but also contribute the lung pathology (Haick et al, 2014).…”