The Gram negative coccobacillus Acinetobacter baumannii has become an increasingly prevalent cause of hospital-acquired infections in recent years. The majority of clinical A. baumannii isolates display high-level resistance to antimicrobials, which severely compromises our capacity to care for patients with A. baumannii disease. Neutrophils are of major importance in the host defense against microbial infections. However, the contribution of these cells of innate immunity in host resistance to cutaneous A. baumannii infection has not been directly investigated. Hence, we hypothesized that depletion of neutrophils increases severity of bacterial disease in an experimental A. baumannii murine wound model. In this study, the Ly-6G-specific monoclonal antibody (mAb), 1A8, was used to generate neutropenic mice and the pathogenesis of several A. baumannii clinical isolates on wounded cutaneous tissue was investigated. We demonstrated that neutrophil depletion enhances bacterial burden using colony forming unit determinations. Also, mAb 1A8 reduces global measurements of wound healing in A. baumannii-infected animals. Interestingly, histological analysis of cutaneous tissue excised from A. baumannii-infected animals treated with mAb 1A8 displays enhanced collagen deposition. Furthermore, neutropenia and A. baumannii infection alter pro-inflammatory cytokine release leading to severe microbial disease. Our findings provide a better understanding of the impact of these innate immune cells in controlling A. baumannii skin infections.

The prevalence of methamphetamine (METH) use is estimated at ∼35 million people worldwide, with over 10 million users in the United States. Chronic METH abuse and dependence predispose the users to participate in risky behaviors that may result in the acquisition of HIV and AIDS-related infections.Cryptococcus neoformansis an encapsulated fungus that causes cryptococcosis, an opportunistic infection that has recently been associated with drug users. METH enhancesC. neoformanspulmonary infection, facilitating its dissemination and penetration into the central nervous system in mice.C. neoformansis a facultative intracellular microorganism and an excellent model to study host-pathogen interactions. METH compromises phagocyte effector functions, which might have deleterious consequences on infection control. In this study, we investigated the role of METH in phagocytosis and antigen processing by J774.16 macrophage- and NR-9460 microglia-like cells in the presence of a specific IgG1 toC. neoformanscapsular polysaccharide. METH inhibits antibody-mediated phagocytosis of cryptococci by macrophages and microglia, likely due to reduced expression of membrane-bound Fcγ receptors. METH interferes with phagocytic cells’ phagosomal maturation, resulting in impaired fungal control. Phagocytic cell reduction in nitric oxide production during interactions with cryptococci was associated with decreased levels of tumor necrosis factor alpha (TNF-α) and lowered expression of Fcγ receptors. Importantly, pharmacological levels of METH in human blood and organs are cytotoxic to ∼20% of the phagocytes. Our findings suggest that METH abrogates immune cellular and molecular functions and may be deadly to phagocytic cells, which may result in increased susceptibility of users to acquire infectious diseases.

Insulin is a peptide hormone produced in the pancreas that is crucial in regulating systemic glucose homeostasis and energy balance. Diabetes mellitus is an endocrine disease that can be broken down into two subtypes. Type I diabetes is low to non‐measurable amounts of insulin being produced by the pancreas consequent to cellular damage. Type II diabetes is caused by insulin resistance and later, decreased insulin secretion. Both conditions lead to hyperglycemia and impaired insulin signaling throughout the body if left untreated. Numerous studies have shown that insulin signaling controls several metabolic pathways in peripheral insulin‐sensitive tissues, such as liver, adipose tissue, and muscle. Among them, autophagy is one of the most potent pathways suppressed by insulin. Autophagy is a molecular mechanism by which cells recycle the damaged or outdated components, including proteins and lipids, to alleviate cellular stresses. In addition, during the fasting state, autophagy acts as a “metabolic rescuing” pathway to degrade non‐essential proteins, providing free amino acids for the synthesis of essential proteins. Conversely, when nutrients are abundant postprandially, insulin potently suppresses this “self‐eating” process in cells. While studies have demonstrated the important role of insulin signaling on the autophagic pathway in peripheral tissues, whether insulin signaling contributes to the regulation of the autophagic pathway in the central nervous system remains elusive. Here, we investigate the role of insulin stimulation on autophagy in mouse astrocytes, the most abundant glial cells in the brain. We show that following insulin stimulation (100 nM, 6 h), the transcription of the critical genes involved in autophagic pathway, including p62, Ulk1/2, several Atg genes, are all dramatically decreased. Consistently, the protein levels of p62, Ulk1/2, as well as LC3, are all reduced following insulin stimulation, indicating suppression of the autophagic process. The effect of insulin signaling on the transcriptional regulation is potent, since 1 nM of insulin is sufficient to suppress many of the critical autophagic genes. To confirm whether insulin suppresses cellular autophagy in astrocytes through insulin receptors, we assessed the expression of autophagic genes following insulin stimulation in both wild‐type (WT) and insulin receptor knockout (IRKO) astrocytes. Compared with WT astrocytes, insulin partially suppresses the expression of autophagic genes in IRKO astrocytes, indicating insulin also can signal through the IGF‐1 receptor in astrocytes. In summary, insulin signaling potently suppresses the autophagic process in astrocytes. This connection between autophagy gene transcription and insulin levels may be an important mechanism for the CNS‐related complications in diabetic patients.