The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on timing with respect to the disease course. Azithromycin is an immunomodulatory drug that has been shown to have antiviral effects and potential benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined for azithromycin which could provide efficacy during the late stages of the disease, including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, induction of regulatory functions of macrophages, and alterations in autophagy. Here we review the published evidence of these mechanisms along with the current clinical use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential impact of azithromycin on the immune response to COVID-19, as well as caution against immunosuppressive and off-target effects including cardiotoxicity in these patients. While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 immune response requires additional characterization so as to better define its role in individualized therapy.

Type I IFN (IFNα/β) is thought to enhance growth of the foodborne intracellular pathogen Listeria monocytogenes (Lm) by promoting mechanisms that dampen innate immunity to infection. However, the type I IFN response has been studied primarily using methods that bypass the stomach and, therefore, fail to replicate the natural course of Lm infection. In this study, we compared i.v. and foodborne transmission of Lm in mice lacking the common type I IFN receptor (IFNAR1−/−). Contrary to what was observed using i.v. infection, IFNAR1−/− and wild type mice had similar bacterial burdens in the liver and spleen following foodborne infection. Splenocytes from wild type mice infected intravenously produced significantly more IFNβ than those infected by the foodborne route. Consequently, the immunosuppressive effects of type I IFN signaling, which included T cell death, increased IL-10 secretion, and repression of neutrophil recruitment to the spleen, were all observed following i.v., but not foodborne transmission of Lm. Type I IFN was also previously shown to cause a loss of responsiveness to IFNγ through down-regulation of the receptor IFNGR1 on macrophages and dendritic cells. However, we detected a decrease in surface expression of IFNGR1 even in the absence of IFNα/β signaling, suggesting that in vivo, this infection-induced phenotype is not type I IFN-dependent. These results highlight the importance of using the natural route of infection for studies of host-pathogen interactions and suggest that the detrimental effects of IFNα/β signaling on the innate immune response to Lm may be an artifact of the i.v. infection model.

Inbred mouse strains differ in their susceptibility to infection with the facultative intracellular bacterium , largely due to delayed or deficient innate immune responses. Previous antibody depletion studies suggested that neutrophils (polymorphonuclear leukocytes [PMN]) were particularly important for clearance in the liver, but the ability of PMN from susceptible and resistant mice to directly kill has not been examined. In this study, we showed that PMN infiltrated the livers of BALB/c/By/J (BALB/c) and C57BL/6 (B6) mice in similar numbers and that both cell types readily migrated toward leukotriene B4 in an chemotaxis assay. However, CFU burdens in the liver were significantly higher in BALB/c mice than in other strains, suggesting that PMN in the BALB/c liver might not be able to clear as efficiently as B6 PMN. Unprimed PMN harvested from either BALB/c or B6 bone marrow killed directly, and pretreatment with autologous serum significantly enhanced killing efficiency for both. were internalized within 10 min and rapidly triggered intracellular production of reactive oxygen species in a dose-dependent manner. However, PMN from gp91-deficient mice also readily killed , which suggested that nonoxidative killing mechanisms may be sufficient for bacterial clearance. Together, these results indicate that there is not an intrinsic defect in the ability of PMN from susceptible BALB/c mice to kill and further suggest that if PMN function is impaired in BALB/c mice, it is likely due to locally produced modulating factors present in the liver during infection.

Listeria monocytogenes is one of several enteric microbes that is acquired orally, invades the gastric mucosa, and then disseminates to peripheral tissues to cause systemic disease in humans. Intravenous (i.v.) inoculation of mice with L. monocytogenes has been the most widely-used small animal model of listeriosis over the past few decades. The infection is highly reproducible and has been invaluable in deciphering mechanisms of adaptive immunity in vivo, particularly CD8+ T cell responses to intracellular pathogens. However, the i.v. model completely bypasses the gut phase of the infection. Recent advances in generating both humanized mice and murinized bacteria, as well as the development of a foodborne route of transmission has reignited interest in studying oral models of listeriosis. In this review, we analyze previously published reports to highlight both the similarities and differences in tissue colonization and host response to infection using either oral or i.v. inoculation.

Atherosclerosis is responsible for a large percentage of all-cause mortality worldwide, but it is only now beginning to be understood as a complex disease process involving metabolic insult, chronic inflammation, and multiple immune mechanisms. Abs targeting apolipoprotein A-I (ApoA-I) have been found in patients with cardiovascular disease, autoimmune conditions, as well as those with no documented history of either. However, relatively little is known about how these Abs are generated and their relationship to diet and sex. In the current study, we modeled this aspect of autoimmunity using anti-ApoA-I immunization of male and female C57BL/6 mice. Unexpectedly, we found that autoantibodies directed against a single, previously unknown, epitope within the ApoA-I protein developed irrespective of immunization status or dyslipidemia in mice. When total IgG subclasses were analyzed over the course of time, we observed that rather than driving an increase in inflammatory IgG subclasses, consumption of Western diet suppressed agedependent increases in IgG2b and IgG2c in male mice only. The lack of change observed in female mice suggested that diet and sex might play a combined role in Th1/Th2 balance and, ultimately, in immunity to pathogen challenge. This report demonstrates the need for inclusion of both sexes in studies pertaining to diet and aging and suggests that further study of immunogenic epitopes present in ApoA-I is warranted. ImmunoHorizons, 2020, 4: 455-463.

PGE 2 is a lipid-signaling molecule with complex roles in both homeostasis and inflammation. Depending on the cellular context, PGE 2 may also suppress certain immune responses. In this study, we tested whether PGE 2 could inhibit bacterial killing by polymorphonuclear neutrophils (PMN) using a mouse model of foodborne listeriosis. We found that PGE 2 pretreatment decreased the ability of PMN harvested from the bone marrow of either BALB/cByJ or C57BL/6J mice to kill Listeria monocytogenes in vitro. PGE 2 treatment slowed the migration of PMN toward the chemoattractant leukotriene B4, decreased uptake of L. monocytogenes by PMN, and inhibited the respiratory burst of PMN compared with vehicle-treated cells. When immune cells were isolated from the livers of infected mice and tested directly ex vivo for the presence of PGE 2 , BALB/cByJ cells produced significantly more than C57BL/6J cells. Together, these data suggest that robust PGE 2 production can suppress PMN effector functions, leading to decreased bacterial killing, which may contribute to the innate susceptibility of BALB/cByJ mice to infection with the facultative intracellular bacterial pathogen L. monocytogenes.

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Non-viral vectors for in vivo delivery of plasmid DNA rely on optimized formulations to achieve robust transgene expression. Several cationic lipids have been developed to deliver nucelic acids, but most...