The Interferon-Induced Gene Ifi27l2a is Active in Lung Macrophages and Lymphocytes After Influenza A Infection but Deletion of Ifi27l2a in Mice Does Not Increase Susceptibility to Infection

Abstract

Interferons represent one of the first and essential host defense mechanisms after infection, and the activation of the IFN-pathway results in the transcriptional activation of hundreds of interferon-stimulated genes. The alpha-inducible protein 27 like 2A (Ifi27l2a) gene (human synonym: ISG12) is strongly up-regulated in the lung after influenza A infection in mice and has been shown in gene expression studies to be highly correlated to other activated genes. Therefore, we investigated the role of Ifi27l2a for the host defense to influenza A infections in more detail. RT-PCR analyses in non-infected mice demonstrated that Ifi27l2a was expressed in several tissues, including the lung. Detailed analyses of reporter gene expression in lungs from Ifi27l2a-LacZ mice revealed that Ifi27l2a was expressed in macrophages and lymphocytes but not in alveolar cells or bronchiolar epithelium cells. The number of macrophages and lymphocyte strongly increased in the lung after infection, but no significant increase in expression levels of the LacZ reporter gene was found within individual immune cells. Also, no reporter gene expression was found in bronchiolar epithelial cells, alveolar cells or infiltrating neutrophils after infection. Thus, up-regulation of Ifi27l2a in infected lungs is mainly due to the infiltration of macrophages and lymphocytes. Most surprisingly, deletion of Ifi27l2a in mouse knock-out lines did not result in increased susceptibility to infections with H1N1 or H7N7 influenza A virus compared to wild type C57BL/6N mice, suggesting a less important role of the gene for the host response to influenza infections than for bacterial infections.

M1 macrophage features in severe Plasmodium falciparum malaria patients with pulmonary oedema

“…Results demonstrated the accumulation of M1 macrophages in the lung of severe P. falciparum malaria patients, especially in the PE group as demonstrated by an increase in CD40 expressing cells. Similar findings were documented in mice lung infected with Escherichia coli [31], in lung-induced chronic obstructive pulmonary disease (COPD) [16], and in viral infection in mice [14]. In addition to M1 being associated with accumulation of haemozoin and the occurrence of acute lung injury, polarization of macrophages to the M1 subtype is responsible for controlling infectious diseases during the acute phase.…”

M1 macrophage activation in severe Plasmodium falciparum malaria patients with pulmonary oedema

“…Results demonstrated the accumulation of M1 macrophages in the lung of severe P. falciparum malaria patients, especially in the PE group as demonstrated by an increase in CD40 expressing cells. Similar findings were documented in mice lung infected with E. coli [29], in lung-induced chronic obstructive pulmonary disease (COPD) [14], and in viral infection in mice [12]. In addition to M1 being associated with accumulation of haemozoin and the occurrence of acute lung injury, polarisation of macrophages to the M1 subtype is responsible for controlling infectious diseases during the acute phase.…”

“…The polarisation of M1 and M2 macrophages are important for disease regulation. Previous studies have documented that activated macrophages are prominent in lung infection with bacteria [11] and viruses [12,13] as well as in lungs from smokers and chronic obstructive pulmonary disease (COPD) [14]. The main purpose of this study was to investigate the status of lung macrophages, as to M1/M2 subtypes in severe P. falciparum malaria patients with and without PE.…”

The Interferon-Stimulated Gene Ifi27l2a Restricts West Nile Virus Infection and Pathogenesis in a Cell-Type- and Region-Specific Manner

“…Ifi27l2a Ϫ/Ϫ mice have been investigated in other contexts. Although Ifi27l2a was identified as an upregulated ISG in lung tissue following IAV infection (63), Ifi272la Ϫ/Ϫ C57BL/6 mice did not sustain higher levels of viral burden or altered pathology in the lungs of infected animals (33). In another Ifi27l2a Ϫ/Ϫ mouse of mixed genetic background, gene-deficient animals were protected against cecal ligation-induced sepsis, lipopolysaccharide (LPS) endotoxemia, and vascular injury after arterial ligation (24,35).…”

“…Ifi27l2a and its closest orthologs have been evaluated as candidate antiviral genes. Despite the strong upregulation of Ifi27l2a mRNA in lung tissues, largely as a result of infiltration of immune cells, Ifi27l2a Ϫ/Ϫ mice were not more susceptible to influenza A virus (IAV) infection than wild-type (WT) mice (33). In contrast, ectopic expression of human IFI27 inhibited HCV and Newcastle disease virus (NDV) infection in hepatocellular carcinoma cells; reciprocally, gene silencing of IFI27 resulted in increased HCV and NDV infection (28,34).…”