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Background: Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of immunity underlying an absence of blood myeloid mononuclear cells, intracerebral calcifications, and multiple infections. Only three unrelated patients have been reported. Materials and Methods: We studied an Argentinian child with multiple infectious diseases and severe pulmonary alveolar proteinosis (PAP). We performed whole-exome sequencing (WES) and characterized his condition by genetic, immunological, and clinical means. Results: The patient was born and lived in Argentina. He had a history of viral pulmonary diseases, disseminated disease due to bacillus Calmette-Guérin (BCG), PAP, and cerebral calcifications. He died at the age of 10 months from refractory PAP. WES identified two compound heterozygous variants in IRF8: c.55del and p.R111*. In an overexpression system, the p.R111* cDNA was loss-of-expression, whereas the c.55del cDNA yielded a protein with a slightly lower molecular weight than the wild-type protein. The mutagenesis of methionine residues downstream from c.55del revealed a re-initiation of translation. However, both variants were loss-of-function in a luciferase assay, suggesting that the patient had AR complete IRF8 deficiency. The patient had no blood monocytes or dendritic cells, associated with neutrophilia, and normal counts of NK and other lymphoid cell subsets. Conclusion: We describe the fourth patient with AR complete IRF8 deficiency. This diagnosis should be considered in children with PAP, which is probably due to the defective development or function of alveolar macrophages. [ABSTRACT FROM AUTHOR]

Leukotrienes (LTs) produced from arachidonic acid by the action of 5-lipoxygenase (5-LO) are classical mediators of inflammatory responses. However, studies published in the literature regarding these mediators are contradictory and it remains uncertain whether these lipid mediators play a role in host defense against the fungal pathogen Paracoccidioides brasiliensis. To determine the involvement of LTs in the host response to pulmonary infection, wild-type and LT-deficient mice by targeted disruption of the 5-lipoxygenase gene (knockout mice) were studied following intratracheal challenge with P. brasiliensis yeasts. The results showed that infection is uniformly fatal in 5-LO-deficient mice and the mechanisms that account for this phenotype are an exacerbated lung injury and higher fungal pulmonary burden. Genetic ablation or pharmacological inhibition of LTs resulted in lower phagocytosis and fungicidal activity of macrophages in vitro, suggesting that deficiency in fungal clearance seems to be secondary to the absence of activation in 5-LO−/− macrophages. Exogenous LTB4 restored phagocytosis and fungicidal activity of 5-LO−/− macrophages. Moreover, P. brasiliensis killing promoted by LTB4 was dependent on nitric oxide (NO) production by macrophages. Taken together, these results reveal a fundamental role for 5-LO-derived LTB4 in the protective response to P. brasiliensis infection and identify relevant mechanisms for the control of fungal infection during the early stages of the host immune response. Author Summary: Paracoccidioidomycosis is a deep mycosis that is endemic in Latin America, mostly affecting rural workers of Argentina, Colombia, Venezuela and Brazil. Paracoccidioides brasiliensis infection is acquired upon the inhalation of airborne propagules derived from the saprophytic mycelium form of the fungus. Once in the lungs, P. brasiliensis converts to its parasitic yeast form and interacts with alveolar macrophages. This phagocytic cell is specialized in secreting cytokines, lipid mediators, and microbicidal molecules that control the fungal growth. Among the lipid mediators generated by macrophages, 5-LO-derived leukotrienes play an important role in lung innate immunity and are known to be important for neutrophil recruitment and activation. Here, we evaluated whether leukotrienes are involved in the immune response in a murine model of P. brasiliensis infection. 5-LO-deficient mice exhibited high mortality, severe lung pathogenesis and increased fungal burden in the lungs, associated with less activation of macrophages, resulting in lower phagocytosis and P. brasiliensis killing. These results reveal for the first time that endogenous production of leukotrienes, especially LTB4, is important for assembling a protective immune response of the host against P. brasiliensis. [ABSTRACT FROM AUTHOR]