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The present research summarizes the protective and immunomodulatory activity of hypothalamic proline-rich polypeptide galarmin against methicillin-resistant Staphylococcus aureus (MRSA). The protective effect of galarmin was shown on MRSA-infected animals' survival and weight loss recovery. The immunological impact of galarmin was evaluated in terms of immunocompetent cell recruitment, serum immunoglobulins, complement components C3 and C4, and pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, IL-1b, TNFa, and KC) secretion. Galarmin efficiently protects mice against lethal MRSA infection (100% of survival vs. 0% in the untreated group) when intramuscularly injected 24 h before infection and during the 1-h post-infection period at a concentration of 1 μg per mouse, while its higher concentrations (5 and 10 μg) were protective when injected in parallel to the infection process. The protective effect of galarmin was not due to a direct effect on MRSA, but should be attributed to an action on the host response to infection. Galarmin significantly increased and modulated the levels of IL-6, IL-8, IL-1b, IL-10, and KC in both peritoneal lavages and blood, leukocyte and platelet counts, lymphocytes percentage, serum IgM and IgG, and complement C3 and C4 components secretion. The experimental results allow concluding that galarmin is a powerful immunomodulatory and protective agent for the in vivo prophylaxis and treatment of MRSA-induced infection. [ABSTRACT FROM AUTHOR]