Experimental Myocarditis Induced in Mice by Infection with Influenza A 2 Virus

The Journal of Immunology

Deng

Jones

et al. 2009

286

308

The clinical response to influenza infection ranges from mild disease to severe pneumonia and it remains unclear whether the inflammatory response to infection is protective or pathogenic. We have defined a novel role for neutrophils in ameliorating lung injury during influenza infection, thereby limiting development of severe disease. Infection of neutrophil-depleted mice with influenza virus HKx31 (H3N2) led to rapid weight loss, pneumonia, and death. Neutropenia was associated with enhanced virus replication in the respiratory tract; however, viral titers were declining at the time of death, leading us to investigate other factors contributing to mortality. In addition to thymic atrophy, lymphopenia, and viremic spread, depletion of neutrophils led to exacerbated pulmonary inflammation, edema, and respiratory dysfunction. Thus, while it is well established that neutrophils contribute to lung injury in a range of pathological conditions, reduced numbers or impaired neutrophil function can facilitate progression of mild influenza to severe clinical disease.

Section: Discussionmentioning

confidence: 42%

Neutrophils Ameliorate Lung Injury and the Development of Severe Disease during Influenza Infection

The Journal of Immunology

Deng

Jones

et al. 2009

286

308

“…Systemic manifestations, such as myocarditis, leukopenia, and thymic atrophy, have been associated with severe clinical disease during influenza virus infections (13,17,35,54). First, infectious virus was not consistently recovered from the hearts and brains of CL-LIP-treated mice, and we did not detect evidence of edema (wet/dry ratio) in hearts recovered from Mdepleted mice, suggesting that myocarditis was not a major factor contributing to severe disease.…”

Section: Severe Clinical Disease Following Bjx109 Infection Of Mdeplementioning

confidence: 62%

Critical Role of Airway Macrophages in Modulating Disease Severity during Influenza Virus Infection of Mice

Pickett

Rooijen

et al. 2010

J Virol

220

255

Airway macrophages provide a first line of host defense against a range of airborne pathogens, including influenza virus. In this study, we show that influenza viruses differ markedly in their abilities to infect murine macrophages in vitro and that infection of macrophages is nonproductive and no infectious virus is released. Virus strain BJx109 (H3N2) infected macrophages with high efficiency and was associated with mild disease following intranasal infection of mice. In contrast, virus strain PR8 (H1N1) was poor in its ability to infect macrophages and highly virulent for mice. Depletion of airway macrophages by clodronate-loaded liposomes led to the development of severe viral pneumonia in BJx109-infected mice but did not modulate disease severity in PR8-infected mice. The severe disease observed in macrophage-depleted mice infected with BJx109 was associated with exacerbated virus replication in the airways, leading to severe airway inflammation, pulmonary edema, and vascular leakage, indicative of lung injury. Thymic atrophy, lymphopenia, and dysregulated cytokine and chemokine production were additional systemic manifestations associated with severe disease. Thus, airway macrophages play a critical role in limiting lung injury and associated disease caused by BJx109. Furthermore, the inability of PR8 to infect airway macrophages may be a critical factor contributing to its virulence for mice.

“…Severe influenza infections are associated with vascular leak and pulmonary edema (26,33) as well as systemic manifestations, including leukopenia and thymic atrophy (43)(44)(45)(46). Compared to mice infected with RG-Brazil WT, high levels of total BAL protein were recovered from RG-Brazil 24-infected mice (Fig.…”

Section: Vascular Leak Pulmonary Edema and Systemic Responses Follomentioning

confidence: 99%

Specific Sites of N-Linked Glycosylation on the Hemagglutinin of H1N1 Subtype Influenza A Virus Determine Sensitivity to Inhibitors of the Innate Immune System and Virulence in Mice

The Journal of Immunology

Brööks

Reading

2011

Oligosaccharides on the hemagglutinin (HA) and neuraminidase of influenza A virus (IAV) are a target for recognition by lectins of the innate immune system, including soluble surfactant protein-D and the macrophage mannose receptor on airway macrophages. Glycans attached to the head of H1 subtype of IAV differ markedly in number and location. A reverse genetic approach was used to define the importance of particular N-glycosylation sites on H1 in determining sensitivity to innate immune defenses and virulence in mice. The HA of A/PR/8/34 (PR8, H1N1) and A/Brazil/11/78 (Brazil, H1N1) express zero and four glycosylation sites on the head of HA, respectively. Site-directed mutagenesis was used to add (PR8) or delete (Brazil) glycosylation sites, and IAV expressing wild-type or mutant HA were generated on a PR8 backbone. Addition or removal of particular glycans modulated sensitivity to mouse lung fluids but was not a major factor determining susceptibility of airway macrophages to infection. PR8 is a mouse-adapted virus, and mutations in multiple IAV genes have been shown to contribute to virulence, yet addition of glycosylation to PR8 HA was sufficient to attenuate disease. In contrast, removal of glycans from Brazil HA resulted in severe disease and death. These studies provide insight regarding the mechanisms by which IAV can induce disease in mice. Moreover, reduced glycosylation of HA is likely to be an important factor associated with adaptation of human IAV to growth in mouse lung.