Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc–FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell–Morell receptors, which is fundamentally different from the classical Fc–FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP.

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The functional role of respiratory microbiota has attracted an accumulating attention recently. However, the role of respiratory microbiome in lung carcinogenesis is mostly unknown. Our study aimed to characterize and compare bilateral lower airway microbiome of lung cancer patients with unilateral lobar masses and control subjects. Protected bronchial specimen brushing samples were collected from 24 lung cancer patients with unilateral lobar masses (paired samples from cancerous site and the contralateral noncancerous site) and 18 healthy controls undergoing bronchoscopies and further analyzed by 16S rRNA amplicon sequencing. As results, significant decreases in microbial diversity were observed in patients with lung cancer in comparison to the controls, alpha diversity steadily declined from healthy site to noncancerous to cancerous site. Genus Streptococcus was significantly more abundant in cancer cases than the controls, while Staphylococcus was more abundant in the controls. The area under the curve of genus Streptococcus used to predict lung cancer was 0.693 (sensitivity = 87.5%, specificity = 55.6%). The abundance of genus Streptococcus and Neisseria displayed an increasing trend whereas Staphylococcus and Dialister gradually declined from healthy to noncancerous to cancerous site. Collectively, lung cancer-associated microbiota profile is distinct from that found in healthy controls, and the altered cancer-associated microbiota is not restricted to tumor tissue. The genus Streptococcus was abundant in lung cancer patients and exhibited moderate classification potential. The gradual microbiota profile shift from healthy site to noncancerous to paired cancerous site suggested a change of the microenvironment associated with the development of lung cancer.

Humans are infected with a variety of acute and chronic pathogens over the course of their lives, and pathogen-driven selection has shaped the immune system of humans. The same is likely true for mice. However, laboratory mice we use for most biomedical studies are bred in ultra-hygienic environments, and are kept free of specific pathogens. We review recent studies that indicate that pathogen infections are important for the basal level of activation and the function of the immune system. Consideration of these environmental exposures of both humans and mice can potentially improve mouse models of human disease.

Legionella pneumophila is an opportunistic intracellular pathogen that causes sporadic and epidemic cases of Legionnaires' disease. Emerging data suggest that Legionella infection involves the subversion of host phosphoinositide (PI) metabolism. However, how this bacterium actively manipulates PI lipids to benefit its infection is still an enigma. Here, we report that the L. pneumophila virulence factor SidF is a phosphatidylinositol polyphosphate 3-phosphatase that specifically hydrolyzes the D3 phosphate of PI(3,4)P 2 and PI(3,4,5)P 3 . This activity is necessary for anchoring of PI(4)Pbinding effectors to bacterial phagosomes. Crystal structures of SidF and its complex with its substrate PI(3,4)P 2 reveal striking conformational rearrangement of residues at the catalytic site to form a cationic pocket that specifically accommodates the D4 phosphate group of the substrate. Thus, our findings unveil a unique Legionella PI phosphatase essential for the establishment of lipid identity of bacterial phagosomes.phosphoinositide signaling | phagocytosis | membrane trafficking | type IV secretion system | virulence factor

Immune thrombocytopenia (ITP) is characterized by platelet clearance mediated primarily by autoantibodies against the platelet GPIIbIIIa and/or GPIbα. Steroid therapy is a first‐line treatment for ITP. However, some patients are refractory to this therapy and currently no method can predict which patients will respond. To evaluate whether steroids are equally efficacious in treating patients with ITP caused by anti‐GPIIbIIIa versus anti‐GPIbα antibodies, we performed a retrospective study on 176 newly diagnosed patients with acute ITP who had severe bleeding symptoms and were admitted as resident patients to the hospital. The patients were treated first with intravenous administration of high‐dose dexamethasone (DXM), followed by oral administration of prednisone. Response to therapy was observed in a majority of patients with antibodies specific for GPIIbIIIa (31/43) or without detectable antibodies against either GPIIbIIIa or GPIbα (36/45). In contrast, the steroid response was significantly lower in patients with anti‐GPIbα antibodies (9/34) or with antibodies against both GPIbα and GPIIbIIIa (16/54). The preliminary findings of this study suggest that in future prospective clinical trials including corticosteroids, the anti‐GPIbα, and ‐GPIIbIIIa status should be assessed in order to test its potential relevance in deciding future treatments. © Wiley Periodicals, Inc.

DA-HAIs in the ICUs of Shanghai pose a far greater threat to patient safety than in ICUs in the USA. This is particularly the case for the VAP rate, which is much higher than the rates found in developed countries. Active infection control programs that carry out infection surveillance and implement prevention guidelines can improve patient safety and must become a priority.

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