Innate Immunity in Murine

Macrophages

 * CI causes impairment in the recruitment of AMs due to decreased production of the chemokine CCL2 (NAKAMURA; DAVIS; WEISER, 2011).
 * Resident AM depletion occurs during IV infection: 90% of resident AMs were lost in the first week after IV, whereas the remaining cells had a necrotic phenotype. CI during the AM depletion phase caused significant body weight loss and mortality. Early AM-mediated bacterial clearance was significantly impaired in IV-infected mice. Among other potential effects, this establishes a niche for secondary SP infection by altering early cellular innate immunity in the lungs, resulting in SP outgrowth and lethal pneumonia (GHONEIM; THOMAS; MCCULLERS, 2013).
 * In vivo neutralization of highly induced AM inflammatory protein 2 did not affect clinical outcome, bacterial loads, or lung immunopathology.(DAMJANOVIC et al., 2013)
 * Virus-induced suppression of pulmonary phagocytic defenses is associated with defects in the intracellular processing of bacteria by AMs. These data demonstrated that virus-induced suppression of intrapulmonary killing of bacteria involves functional lesions that retard the ingestion of inhaled organisms by AMs and inhibit intracellular processing by degradative lysosomal enzymes by interfering with phagosome-lysosome fusion (JAKAB; WARR; SANNES, 1980).
 * Viral titers initially rebound and then decline slowly. Bacterial titers rapidly rise to high levels and remain elevated. Viral titers rebound in the presence of bacteria due to enhanced viral release from infected cells, and that bacterial titers increase due to AM impairment (SMITH et al., 2013).
 * Role for PLY in SP-mediated protection by maintaining AMs as “gatekeepers” against virus-induced immunopathology. Colonization with the PLY-sufficient SP strain induces expression of the immune-suppressive enzyme arginase 1 in AMs and correlates with attenuated recruitment and function of pulmonary inflammatory cells (WOLF et al., 2014).
 * The cytokines which induce alternatively activated AMs (IL-4 and IL-13) and the expression of genes associated with them (Arginase-1, FIZZ1, and YM1) were elevated after mice adapted IV infection (CHEN et al., 2012).
 * Pulmonary AM are induced during IV infection and may contribute to the elicitation of hypersusceptibility to a secondary bacterial infection (CHEN et al., 2012).
 * CI impairs the recruitment of AMs, which are required for SP clearance, due to decreased production of the chemokine CCL2 (NAKAMURA; DAVIS; WEISER, 2011).
 * Although H1N1 IV infection of naive mice induced intensive phagocyte recruitment, pulmonary innate defense against secondary SP infection was severely suppressed (SUN et al., 2011).
 * AM inflammatory protein 2 was linked to the poor clinical outcome of CI (DAMJANOVIC et al., 2013).
 * Production of IFN-γ after IV infection alters the activation status of local AMs, allowing them to enhance adaptive antiviral responses through increased MHC expression while repressing their ability to mediate innate immunity (SUN; METZGER, 2008).

Neutrophils

 * Significant neutrophil accumulation in the lungs of SP-infected mice (MCNAMEE; HARMSEN, 2006).
 * A prior IV infection of 6 days may compromise neutrophil function, resulting in increased susceptibility to a SP infection (MCNAMEE; HARMSEN, 2006).
 * In vivo neutrophil depletion did not alter the clinical outcome and bacterial burden, although it moderately improved lung immunopathology (DAMJANOVIC et al., 2013).
 * Increased susceptibility to secondary bacterial pneumonia is at least in part caused by reduced neutrophil function in the lungs (VAN DER SLUIJS et al., 2004).
 * Neutrophil extracellular traps (NETs) do not participate in killing of SP in vivo and in vitro (MOORTHY et al., 2013).
 * The less effective response in WT mice is attributable to impaired production of neutrophil chemoattractants KC (also known as Cxcl1) and Mip2 (also known as Cxcl2) following secondary challenge with SP. This resulted in inadequate neutrophil responses during the early phase of host defense against secondary bacterial infection (SHAHANGIAN et al., 2009).
 * Neutrophils from the lungs of mice infected with IV for 3 or 6 days exhibited functional impairment in the form of decreased phagocytosis and intracellular reactive oxygen species generation in response to SP (MCNAMEE; HARMSEN, 2006).
 * Elevated concentrations of IL-6, IL-1b, KC, IL-10, and IL-33  and myeloperoxidase levels in lung indicate enhanced neutrophil activity (BLOK et al., 2013).
 * Severe lung neutrophilia and immunopathology were linked to the poor clinical outcome of CI (DAMJANOVIC et al., 2013).
 * The severe pulmonary pathology and excessive neutrophil extracellular traps generation in CI correlated with exaggerated inflammation and damage to the alveolar-capillary barrier (MOORTHY et al., 2013).
 * Ab-mediated neutropenia did not increase SP-susceptibility or compromise the ability to control SP growth (STEGEMANN et al., 2009).

Toll-like Receptors
=> Toll-like Receptors recognize the invasion of micro-organisms and plays a role in innate nonspecific immune responses.
 * Immune mediators play an important role in the pathology of CI through toll-like receptors (METERSKY et al.,2012).
 * Elevated intrapulmonary levels of toll-like receptors were observed in mice inoculated with CI with an interval of 2 days (METERSKY et al., 2012).

TLR7

 * The pattern-recognition receptor (PRR) toll-like receptor 7 is a major sensor for the viral genome (STEGEMANN-KONISZEWSKI et al., 2013).
 * In secondary SP infection during acute IV, TLR7 KO mice showed a fatal outcome similar to WT hosts, despite significantly delayed disease progression (STEGEMANN-KONISZEWSKI et al., 2013).
 * The fatal overall outcome in WT as well as TLR7 KO hosts suggests that processes distinct from TLR7-triggering override the contribution of this single PRR (STEGEMANN-KONISZEWSKI et al., 2013).
 * Lymphopenia forced by TLR7-triggering did not increase SP-susceptibility or compromise the ability to control SP growth (STEGEMANN et al., 2009).

IL1RL1/ST2
=> IL1RL1 is a member of the Toll-like receptor superfamily but, unlike other members of the family, it does not induce an inflammatory response through activation of NF-κB, although it does activate MAP kinases.

=> IL1RL1 is a member of the interleukin 1 receptor family.
 * Interleukin-1 Receptor Like 1 deficiency did not impact on gross lung pathology in either IV or secondary SP pneumonia (BLOK et al., 2013).

UT12

 * Survival rates were significantly increased and body weight loss was significantly decreased by UT12 administration (Toll-like receptor 4 agonistic monoclonal Ab UT12) (TANAKA et al.,2013).
 * The production of inflammatory mediators was significantly suppressed by the administration of UT12.
 * In a histopathological study, pneumonia in UT12-treated mice was very mild compared to that in control mice (TANAKA et al.,2013).
 * UT12 increased antimicrobial defense through the acceleration ofAMrecruitment into the lower respiratory tract induced by c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-kB) pathway-dependent monocyte chemoattractant protein 1 (MCP-1) production (TANAKA et al.,2013).
 * The study indicates that UT12 promoted pulmonary innate immunity and may reduce the severity of severe pneumonia induced by CI with IV and SP (TANAKA et al.,2013).

Platelet-Activating Factor

 * Groups of mice receiving CV-6209, a competitive antagonist of platelet-activating factor receptor (PAFr), had survival rates similar to those of control mice, and lung and blood bacterial titers increased during PAFr inhibition. These data suggest that PAFr-independent pathways are operative (MCCULLERS; REHG, 2002).
 * Although IV enhanced the adherence of SP to respiratory epithelial cells in vitro, chemical or Ab-mediated blockade of the PAFR did not affect adherence. Mice lacking PAFR had similar bacterial loads within the lung compartment when compared to heterozygous littermates and were not protected from secondary SP pneumonia after IV (MCCULLERS et al., 2008).