Tumor progression locus 2 (Tpl2) is a serine-threonine kinase known to promote inflammation in response to various pathogen-associated molecular patterns (PAMPs), inflammatory cytokines and G-protein-coupled receptors and consequently aids in host resistance to pathogens. We have recently shown that Tpl2-/- mice succumb to infection with a low-pathogenicity strain of influenza (x31, H3N2) by an unknown mechanism. In this study, we sought to characterize the cytokine and immune cell profile of influenza-infected Tpl2-/- mice to gain insight into its host protective effects. Although Tpl2-/- mice display modestly impaired viral control, no virus was observed in the lungs of Tpl2-/- mice on the day of peak morbidity and mortality suggesting that morbidity is not due to virus cytopathic effects but rather to an overactive antiviral immune response. Indeed, increased levels of interferon-β (IFN-β), the IFN-inducible monocyte chemoattractant protein-1 (MCP-1, CCL2), Macrophage inflammatory protein 1 alpha (MIP-1α; CCL3), MIP-1β (CCL4), RANTES (CCL5), IP-10 (CXCL10) and Interferon-γ (IFN-γ) was observed in the lungs of influenza-infected Tpl2-/- mice at 7 days post infection (dpi). Elevated cytokine and chemokines were accompanied by increased infiltration of the lungs with inflammatory monocytes and neutrophils. Additionally, we noted that increased IFN-β correlated with increased CCL2, CXCL1 and nitric oxide synthase (NOS2) expression in the lungs, which has been associated with severe influenza infections. Bone marrow chimeras with Tpl2 ablation localized to radioresistant cells confirmed that Tpl2 functions, at least in part, within radioresistant cells to limit pro-inflammatory response to viral infection. Collectively, this study suggests that Tpl2 tempers inflammation during influenza infection by constraining the production of interferons and chemokines which are known to promote the recruitment of detrimental inflammatory monocytes and neutrophils.

Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-␥), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 Ϫ/Ϫ mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 Ϫ/Ϫ mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-␥ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag Ϫ/Ϫ mice, Tpl2 Ϫ/Ϫ CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 Ϫ/Ϫ mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function. KEYWORDS Citrobacter, T helper cells, gastrointestinal infection, intestinal immunity, neutrophilsC itrobacter rodentium is a nonmotile Gram-negative rod that is a natural mouse and gerbil pathogen (1, 2). Upon infection, C. rodentium colonizes the large intestine, primarily the cecum and distal portion of the colon (3), and forms a close association with the epithelium and lamina propria that results in attaching and effacing lesions in the large intestine (4, 5). However, C. rodentium can disseminate out of the intestines and be found in the nasopharynx, lung, heart, liver, and spleen (6). Early innate responses to C. rodentium are associated with recruitment and the antimicrobial functions of neutrophils, macrophages, NK cells, and innate lymphoid cells (7-12). Neutrophils secrete interleukin-17A (IL-17A) and IL-22, promote the production of antimicrobial defensins by epithelial cells, and protect against the development of diarrhea (11,13). The bacterial association with the lamina propria of the large intestine subsequently induces a mixed Th1 and Th17 response associated with IL-12, gamma interferon (IFN-␥), tumor necrosis factor (TNF), . Clearance of the bacteria occurs within 3 weeks in a wild-type host and is dependent upon both CD4 T cell and B cell functions (18, 19).Tumor progression locus 2 (Tpl2; also known as MAP3K8) is a serine-threonine Citation Acuff NV, Li X, Latha K, Nagy T, Watford WT. 2017. Tpl2 promotes innat...

Background: Autoimmune diseases` incidence had increased significantly by 1995-as compared to 1983, by when tubectomy, contraception was being steadily implemented; hence an altruistic correlation was sought after. Methods: Data of 64 people with varied autoimmune diseases spread over 1989-2012 from 7 geographical locations, each separated by ~500 km distance, was tabulated into 3 age groups, namely 20-35 years, 35-50 years, >50 years and association with contraception status, consumption of fish without scales, gills, shell fish, was analyzed by bio informatics, retrospectively in 2012. In 2002, 2003 data of 105 patients from the community and hospital was analyzed for association of contraception status, prevalent diseases and estrogen levels. Results: Contraceptive users demonstrated 15 fold increase in auto-immune diseases among 20-35 years [p <0.0005]; 40 fold increase in auto-immune diseases among 35-50 years [p <0.0005]; 5 fold increase in autoimmune diseases were seen with consumption of fish without scales and gills in non contraceptive users also. Endogenous estrogen was reduced below normal in 61% of patients using contraception [p <0.0005]. Conclusion: The concept is contraception results in smashed fragmentation of Germ Cells, to a centric fragments, ring chromosomes, chromatid breaks, being identified by immune surveillance as foreign, leading to auto immunity; associated reduced endogenous estrogen or androgen, results in defaulted cell cycle, cell metabolism of differentiation, growth, controlled multiplication, degeneration, apoptosis, regeneration, genomic repertoire, leading to impaired immunity; auto-immunity is also produced by consumption of fish without scales and gills due to its toxins mediated cytotoxicity, by molecular mimicry, in non contraceptive users also. Abstinence for 7 days after last menstrual period, prevents exposure of raw endometrial surface to germ cells; abstinence for 45 days after male baby delivery, 90 days after girl baby delivery prevents germ cells exposure to raw placental detached surface and reduces auto immunity.

Background: Patients requiring valve replacement at a younger age, for rheumatic heart disease was apparently increasing after the new age practice of contraception. Methods: In 2012, data of patients referred to tertiary care hospital from two cardiology screening camps conducted in the community, were analyzed for the severity of presentation of rheumatic heart disease and associated contraception status by dividing into the three age groups-20-35 years, 36-50 years, >51 years; ~400 patients attended the camps; 31 female and 2 male patients were referred to the tertiary care hospital for further evaluation and categorized treatment, including valve replacement surgeries; among the 33 referred patients, belonging to the three age groups, the data were analyzed for [if any] correlation of contraception status with severe rheumatic heart disease. 8 randomly chosen males, of the 3 age groups, from a different community, whose life partners had undergone sterilization, were assessed for their serum testosterone levels. Results: Among 20-35 years, 7 female patients with contraception required valve replacement surgeries [p < 0.0005]; among 36-50 years, 20 female patients required valve replacement surgeries [p < 0.0005]; whereas among >51 years, 3 female and 2 male patients without contraception received medical treatment only [p < 0.0005]. Conclusion: Concept is contraception with smashed fragmentation of germ cells, consequent reduced endogenous estrogen and androgen leading to defaulted genomic repertoire, deranged cell metabolism and increased tendency for fibrosis has resulted in increased prevalence of severe valve disease in younger age itself, requiring valve replacement.

The most prominent host response to viral infection is the production of type 1 interferons (T1 IFNs). One host regulator of the T1 IFNs is the serine-threonine kinase, tumor progression locus 2 (TPL2). We have previously demonstrated that Tpl2 −/− mice succumb to infection with a low-pathogenicity influenza A strain (x31), in association with with increased pulmonary levels of interferon-β (IFN-β), chemokine CCL2, and excessive monocyte and neutrophil pulmonary infiltration. TPL2-dependent overexpression of IFN-β has been implicated in enhanced susceptibility to Mycobacterium tuberculosis ; therefore, we examined the role of T1 IFNs in susceptibility of Tpl2 −/− mice to influenza. CCL2 overexpression and monocyte recruitment were normalized in Ifnar1 −/− Tpl2 −/− mice, confirming that TPL2 constrains inflammatory monocyte recruitment via inhibition of the T1 IFN/CCL2 axis. Unexpectedly, excessive neutrophil recruitment in Ifnar1 −/− strains was further exacerbated by simultaneous TPL2 genetic ablation in Ifnar1 −/− Tpl2 −/− by 7 dpi, accompanied by overexpression of neutrophil-regulating cytokines, CXCL1 and IFN-λ. Collectively, our data suggest that TPL2 and T1 IFNs synergize to inhibit neutrophil recruitment. However, treatment with the neutrophil-depleting anti-Ly6G antibody showed only a modest improvement in disease. Analysis of sorted innate immune populations revealed redundant expression of inflammatory mediators among neutrophils, inflammatory monocytes and alveolar macrophages. These findings suggest that targeting a single cell type or mediator may be inadequate to control severe disease characterized by a mixed inflammatory exudate. Future studies will consider TPL2-regulated pathways as potential predictors of severe influenza progression as well as investigate novel methods to modulate TPL2 function during viral infection. Supplementary Information The online version contains supplementary material available at 10.1007/s10753-022-01736-8.