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Kinase activity plays an essential role in the regulation of immune cell defenses against pathogens. The protein kinase CK2 (formerly casein kinase II) is an evolutionarily conserved kinase with hundreds of identified substrates. CK2 is ubiquitously expressed in somatic and immune cells, but the roles of CK2 in regulation of immune cell function remain largely elusive. This reflects the essential role of CK2 in organismal development and limited prior work with conditional CK2 mutant murine models. Here, we generated mice with a conditional (floxed) allele of Csnk2a , which encodes the catalytic CK2α subunit of CK2. When crossed to Lyz2 -cre mice, excision of Csnk2a sequence impaired CK2α expression in myeloid cells but failed to detectably alter myeloid cell development. By contrast, deficiency for CK2α increased inflammatory myeloid cell recruitment, activation, and resistance following systemic Listeria monocytogenes (Lm) infection. Results from mixed chimera experiments indicated that CK2α deficiency in only a subset of myeloid cells was not sufficient to reduce bacterial burdens. Nor did cell-intrinsic deficiency for CK2α suffice to alter accumulation or activation of monocytes and neutrophils in infected tissues. These data suggest that CK2α expression by Lyz2 -expressing cells promotes inflammatory and anti-bacterial responses through effects in trans . Our results highlight previously undescribed suppressive effects of CK2 activity on inflammatory myeloid cell responses and illustrate that cell-extrinsic effects of CK2 can shape inflammatory and protective innate immune responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Larson, Bortell, Illies, Crisler, Matsuda and Lenz.)

Stimulator of interferon genes (STING) plays a central role in innate immune responses to viral and intracellular bacterial infections, and cellular damage. STING is a cytosolic sensor of cyclic dinucleotides (CDNs) including those produced by pathogenic bacteria and those arising endogenously as products of the DNA sensor cGAS (e.g., 2'3' cGAMP). The two most common alternative allelic variants of STING in humans are STING-R71H-G230A-R293Q (STING-HAQ) and STING-R232H that are found in 20.4% and 13.7-17.6% of the population, respectively. To determine the biologic consequences of these genotypic variations, we generated knock-in mice containing the murine equivalents of each variant and studied their responsiveness to CDNs. Homozygous STING-HAQ (R71H-I229A-R292Q) and STING-R231H mice were found to be unresponsive to all exogenous CDNs tested (ci-di-GMP, ci-di-AMP, 3'3' cGAMP and Rp,Rp-CDA). Responses of homozygous STING-HAQ mice to endogenous 2'3' cGAMP was also greatly impaired. However, homozygous STING-R231H mice are fully responsive to 2'3' cGAMP. Analysis of heterozygous mice revealed reduced responsiveness to exogenous and endogenous CDNs in mice carrying a single copy of STING-HAQ, while STING-R231H heterozygous mice exhibit reduced responsiveness to exogenous but not endogenous CDNs. These findings confirm and extend previous reports by demonstrating differing impact of allelic variation of STING on the ability to sense and respond to exogenous vs. endogenous CDNs. Finally, the STING-R231H variant mouse represents a useful tool with which to examine the relative contributions of STING sensing of exogenous and endogenous CDNs in the context of bacterial infections and CDN-based cancer immunotherapeutics., (Copyright © 2020 Walker, Kim, Crisler, Nguyen, Lenz, Cambier and Getahun.)

Bacterial and viral pathogens are predominant causes of pulmonary infections and complications. Morbidity and mortality from these infections is increased in populations that include the elderly, infants, and individuals with genetic disorders such as Down syndrome. Immune senescence, concurrent infections, and other immune alterations occur in these susceptible populations, but the underlying mechanisms that dictate increased susceptibility to lung infections are not fully defined. Here, we review unique features of the lung as a mucosal epithelial tissue and aspects of inflammatory and immune responses in model pulmonary infections and co-infections by influenza virus and Streptococcus pneumoniae . In these models, lung inflammatory responses are a double-edged sword: recruitment of immune effectors is essential to eliminate bacteria and virus-infected cells, but inflammatory cytokines drive changes in the lung conducive to increased pathogen replication. Excessive accumulation of inflammatory cells also hinders lung function, possibly causing death of the host. Some animal studies have found that targeting host modulators of lung inflammatory responses has therapeutic or prophylactic effects in these infection and co-infection models. However, conflicting results from other studies suggest microbiota, sequence of colonization, or other unappreciated aspects of lung biology also play important roles in the outcome of infections. Regardless, a predisposition to excessive or aberrant inflammatory responses occurs in susceptible human populations. Hence, in appropriate contexts, modulation of inflammatory responses may prove effective for reducing the frequency or severity of pulmonary infections. However, there remain limitations in our understanding of how this might best be achieved-particularly in diverse human populations., (Copyright © 2020 Aguilera and Lenz.)

Natural killer (NK) cells can produce IFNγ or IL-10 to regulate inflammation and immune responses but the factors driving NK cell IL-10 secretion are poorly-defined. Here, we identified NK cell-intrinsic STAT3 activation as vital for IL-10 production during both systemic Listeria monocytogenes (Lm) infection and following IL-15 cytokine/receptor complex (IL15C) treatment for experimental cerebral malaria (ECM). In both contexts, conditional Stat3 deficiency in NK cells abrogated production of IL-10. Initial NK cell STAT3 phosphorylation was driven by IL-15. During Lm infection, this required capture or presentation of IL-15 by NK cell IL-15Rα. Persistent STAT3 activation was required to drive measurable IL-10 secretion and required NK cell expression of IL-10Rα. Survival-promoting effects of IL-15C treatment in ECM were dependent on NK cell Stat3 while NK cell-intrinsic deficiency for Stat3, Il15ra , or Il10ra abrogated NK cell IL-10 production and increased resistance against Lm. NK cell Stat3 deficiency did not impact production of IFNγ, indicating the STAT3 activation initiated by IL-15 and amplified by IL-10 selectively drives the production of anti-inflammatory IL-10 by responding NK cells.

Objectives: HIV-exposed uninfected (HEU) infants have higher rates of severe and fatal infections compared with HIV-unexposed (HUU) infants, likely due to immune perturbations. We hypothesized that alterations in natural killer (NK) cell activity might occur in HEU infants and predispose them to severe infections., Design: Case-control study using cryopreserved peripheral blood mononuclear cells (PBMCs) at birth and 6 months from HEU infants enrolled from 2002 to 2009 and HUU infants enrolled from 2011 to 2013., Methods: NK cell phenotype and function were assessed by flow cytometry after 20-h incubation with and without K562 cells., Results: The proportion of NK cells among PBMCs was lower at birth in 12 HEU vs. 22 HUU (1.68 vs. 10.30%, p  < 0.0001) and at 6 months in 52 HEU vs. 72 HUU (3.09 vs. 4.65%, p  = 0.0005). At birth, HEU NK cells demonstrated increased killing of K562 target cells ( p  < 0.0001) and increased expression of CD107a (21.65 vs. 12.70%, p  = 0.047), but these differences resolved by 6 months. Stimulated HEU NK cells produced less interferon (IFN)γ at birth (0.77 vs. 2.64%, p  = 0.008) and at 6 months (4.12 vs. 8.39%, p  = 0.001), and showed reduced perforin staining at 6 months (66.95 vs. 77.30%, p  = 0.0008). Analysis of cell culture supernatants indicated that lower NK cell activity in HEU was associated with reduced interleukin (IL)-12, IL-15, and IL-18. Addition of recombinant human IL-12 to stimulated HEU PBMCs restored IFNγ production to that seen in stimulated HUU cultures., Conclusion: NK cell proportion, phenotype, and function are altered in HEU infants. NK cell cytotoxicity and degranulation are increased in HEU at birth, but HEU NK cells have reduced IFNγ and perforin production, suggesting an adequate initial response, but decreased functional reserve. NK cell function improved with addition of exogenous IL-12, implicating impaired production of IL-12 by accessory cells. Alterations in NK cell and accessory cell function may contribute to the increased susceptibility to infection in HEU infants.

Type I interferons (IFNs) were first described for their ability to protect the host from viral infections and may also have beneficial effects under specific conditions within some bacterial infections. Yet, these pleiotropic cytokines are now known to exacerbate infections by numerous life-threatening bacteria, including the intracellular pathogens Listeria monocytogenes and Mycobacterium tuberculosis. The evidence that such detrimental effects occur during bacterial infections in both animals and humans argues for selective pressure. In this review, we summarize the evidence demonstrating a pro-bacterial role for type I IFNs and discuss possible mechanisms that have been proposed to explain such effects. The theme emerges that type I IFNs act to suppress myeloid cell immune responses. The evolutionary conservation of such anti-inflammatory effects, particularly in the context of infections, suggests they may be important for limiting chronic inflammation. Given the effectiveness of type I IFNs in treatment of certain autoimmune diseases, their production may also act to raise the threshold for activation of immune responses to self-antigens.