Large Scale Comparison of Innate Responses to Viral and Bacterial Pathogens in Mouse and Macaque

Abstract

Viral and bacterial infections of the lower respiratory tract are major causes of morbidity and mortality worldwide. Alveolar macrophages line the alveolar spaces and are the first cells of the immune system to respond to invading pathogens. To determine the similarities and differences between the responses of mice and macaques to invading pathogens we profiled alveolar macrophages from these species following infection with two viral (PR8 and Fuj/02 influenza A) and two bacterial (Mycobacterium tuberculosis and Francisella tularensis Schu S4) pathogens. Cells were collected at 6 time points following each infection and expression profiles were compared across and between species. Our analyses identified a core set of genes, activated in both species and across all pathogens that were predominantly part of the interferon response pathway. In addition, we identified similarities across species in the way innate immune cells respond to lethal versus non-lethal pathogens. On the other hand we also found several species and pathogen specific response patterns. These results provide new insights into mechanisms by which the innate immune system responds to, and interacts with, invading pathogens.

cDREM: Inferring Dynamic Combinatorial Gene Regulation

“…DREM has proven to be successful at modeling several biological processes and systems in multiple organisms, including stress response in yeast and E. coli (Ernst et al, 2007(Ernst et al, , 2008, human and mouse development (Schulz et al, 2013;Roy et al, 2010;Mendoza-Parra et al, 2011), and immune and disease progression Zinman et al, 2011;Laurenti et al, 2013).…”

Differential proteomic analysis of respiratory samples from patients suffering from influenza

“…Several genomic and proteomic studies have also been carried out in influenza-infected macaques [1,42]. In a recent study, Andrea L. Kroeker carried out the differential expression of host protein in primary human bronchial airway epithelial (HBAE) cells and she reported that the down regulated proteins generally belong to cell adhesion and lipid metabolism and up regulated proteins were from the host defense responses against influenza infection [44]. Most proteomic studies investigating the effect of influenza infection have been carried out in different cell lines and primary macrophages.…”

Critical insights into the pathogenesis of clinical isolates of pandemic influenza A(H1N1) 2009 virus in mouse and ferret models.

“…As evidenced above, many viral infections associated with neutrophil infiltration have RNA genomes. Host cells detect RNA viruses primarily through RLR as well as TLR, whereas bacteria rely on a different group of PRRs to detect extracellular PAMPs (327,328,357,505). Because of the importance in diagnostics, many studies have focused on biomarkers that identify bacterial versus viral infection (e.g., (506,507)).…”

“…In short a single reliable biomarker of bacterial versus viral infection has yet to be found. In a recent study, it was among a group of early conserved differentially expressed genes across species (mouse and macaque) and pathogens (IAV and bacterial), all of which were the direct result of an upregulation of ISGs (505). For example, IFNb, IL-1a, IL-6, IL-23a, TIMP1, M-CSF, ISG15, CCL2, CCL5, CXCL10, and CD40 were all common to the early host immune response to lung infection (505).…”

“…In a recent study, it was among a group of early conserved differentially expressed genes across species (mouse and macaque) and pathogens (IAV and bacterial), all of which were the direct result of an upregulation of ISGs (505). For example, IFNb, IL-1a, IL-6, IL-23a, TIMP1, M-CSF, ISG15, CCL2, CCL5, CXCL10, and CD40 were all common to the early host immune response to lung infection (505). The control of signaling through TLR versus cytoplasmic is controlled by complex intracellular adaptor proteins (e.g., allowing the characteristically bacteria-specific TLR4 to signal the upregulation of viral-specific type I interferons (514)), the implications of this require much more research (reviewed in (515)).…”