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Key Points Many Leishmania spp. can cause human disease, with clinical symptoms dependent upon both host- and parasite-related factors. During infection, leishmanial parasites may be phagocytosed by a variety of cells, including neutrophils, monocytes, monocyte-derived dendritic cells (moDCs), macrophages and stromal cells. However, host cell preference and the importance of each cell type to parasite clearance versus parasite persistence may vary following infection by different Leishmania spp. Intracellular Leishmania parasites have multiple ways to manipulate macrophage function, including subverting the control of phagosome biogenesis and maturation. The importance of parasite virulence factors (for example, lipophosphoglycan) in this process is dependent upon leishmanial species and host cell type. Major surface protease (MSP; also known as GP63) of Leishmania spp. has an important role in regulating intracellular survival in some host cells, by cleaving a variety of phosphotyrosine phosphatases such as SRC homology 2 domain phosphotyrosine receptor phosphate (SHP1). MSP may access these cytosolic targets after crossing lipid microdomains in the host cell membrane. Iron has a key role in intracellular survival of leishmanial pathogens, with both host (SLC11A1) and parasite (LIT1) transporters competing to secure this essential resource. Cell-mediated immunity to leishmanial infection is multifactorial, with different models of disease serving to exemplify different aspects, for example, the importance of CD8 + T cells and/or the involvement of moDCs. Parasite persistence and the capacity to induce good vaccine-induced immunity are both strongly influenced by the presence of interleukin-10 (IL-10). There are multiple cellular sources of IL-10 (T helper 1 (T H 1) cells, regulatory T (T Reg ) cells, B cells, macrophages and DCs), but whether each has similar functional significance has yet to be determined. Leishmaniases, affecting over 150 million people worldwide, are caused by insect-borne protists of the genus Leishmania . Here, Kaye and Scott summarize the mechanisms involved in the establishment, survival and persistence of the different Leishmania spp. in their hosts, and highlight the pitfalls associated with a simplistic view of leishmanial pathogenesis. Leishmania is a genus of protozoan parasites that are transmitted by the bite of phlebotomine sandflies and give rise to a range of diseases (collectively known as leishmaniases) that affect over 150 million people worldwide. Cellular immune mechanisms have a major role in the control of infections with all Leishmania spp. However, as discussed in this Review, recent evidence suggests that each host–pathogen combination evokes different solutions to the problems of parasite establishment, survival and persistence. Understanding the extent of this diversity will be increasingly important in ensuring the development of broadly applicable vaccines, drugs and immunotherapeutic interventions.

Protein-energy malnutrition (PEM) is a risk factor for developing visceral leishmaniasis (VL). While nutrient deficiency can impair immunity, its mechanistic impact on protective adaptive immune responses following Leishmania infection remains unknown. To determine the potential negative impacts of malnutrition on anti-parasitic responses in chronic VL, we provided mice with a polynutrient-deficient diet (deficient protein, energy, zinc, and iron) that mimics moderate human malnutrition. The polynutrient-deficient diet resulted in growth stunting and reduced mass of visceral organs and following infection with Leishmania infantum , malnourished-mice harbored more parasites in the spleen and liver. Malnourished and infected mice also had fewer T lymphocytes, with reduced T cell production of IFN-γ required for parasite clearance and enhanced production of the immunosuppressive cytokine, IL-10. To determine if IL-10 was causative in disease progression in the malnourished mice, we treated infected mice with monoclonal antibody α-IL-10R. α-IL-10R treatment reduced the parasite number in malnourished mice, restored the number of T cells producing IFN-γ, and enhanced hepatic granuloma formation. Our results indicate that malnutrition increases VL susceptibility due to defective IFN-γ-mediated immunity attributable to increased IL-10 production.

Early prenatal stress disrupts maternal-to-offspring microbiota transmission and has lasting effects on metabolism, physiology, cognition, and behavior in male mice. Here we show that transplantation of maternal vaginal microbiota from stressed dams into naive pups delivered by cesarean section had effects that partly resembled those seen in prenatally stressed males. However, transplantation of control maternal vaginal microbiota into prenatally stressed pups delivered by cesarean section did not rescue the prenatal-stress phenotype. Prenatal stress was associated with alterations in the fetal intestinal transcriptome and niche, as well as with changes in the adult gut that were altered by additional stress exposure in adulthood. Further, maternal vaginal transfer also partially mediated the effects of prenatal stress on hypothalamic gene expression, as observed after chronic stress in adulthood. These findings suggest that the maternal vaginal microbiota contribute to the lasting effects of prenatal stress on gut and hypothalamus in male mice.

Cutaneous leishmaniasis exhibits a wide spectrum of clinical presentations from self-resolving infections to severe chronic disease. Anti-parasitic drugs are often ineffective in the most severe forms of the disease, and in some cases the magnitude of the disease can result from an uncontrolled inflammatory response rather than unrestrained parasite replication. In these patients, host-directed therapies offer a novel approach to improve clinical outcome. Importantly, there are many anti-inflammatory drugs with known safety and efficacy profiles that are currently used for other inflammatory diseases and are readily available to be used for leishmaniasis. However, since leishmaniasis consists of a wide range of clinical entities, mediated by a diverse group of leishmanial species, host-directed therapies will need to be tailored for specific types of leishmaniasis. There is now substantial evidence that host-directed therapies are likely to be beneficial beyond autoimmune diseases and cancer and thus should be an important component in the armamentarium to modulate the severity of cutaneous leishmaniasis.

Deregulated CD8+ T cell cytotoxicity plays a central role in enhancing disease severity in several conditions. However, we have little understanding of the mechanisms by which immunopathology develops as a consequence of cytotoxicity. Using murine models of inflammation induced by the protozoan parasite leishmania, and data obtained from patients with cutaneous leishmaniasis, we uncovered a previously unrecognized role for NLRP3 inflammasome activation and IL-1β release as a detrimental consequence of CD8+ T cell-mediated cytotoxicity, ultimately resulting in chronic inflammation. Critically, pharmacological blockade of NLRP3 or IL-1β significantly ameliorated the CD8+ T cell-driven immunopathology in leishmania-infected mice. Confirming the relevance of these findings to human leishmaniasis, blockade of the NLRP3 inflammasome in skin biopsies from leishmania-infected patients prevented IL-1β release. Thus, these studies link CD8+ T cell cytotoxicity with inflammasome activation and reveal novel avenues of treatment for cutaneous leishmaniasis, as well as other of diseases where CD8+ T cell-mediated cytotoxicity induces pathology.

Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer 1 , 2 . The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability 3 . Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability 4 – 6 . Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37 . To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material—these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37- dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers. TRIM37 overexpression promotes centrosome dysfunction that drives genomic instability in breast cancer cell lines containing the recurrent 17q23 amplicon, revealing a vulnerability that can be targeted to eliminate cancer cells.

Cutaneous leishmaniasis exhibits a spectrum of clinical presentations dependent upon the parasites’ persistence and host immunopathologic responses. Although cytolytic CD8 T cells cannot control the parasites, they significantly contribute to pathologic responses. In a murine model of cutaneous leishmaniasis, we previously found that NKG2D plays a role in the ability of cytolytic CD8 T cells to promote disease in leishmanial lesions. Here, we investigated whether NKG2D plays a role in human disease. We found that NKG2D and its ligands were expressed within lesions from L . braziliensis -infected patients and that IL-15 and IL-1β were factors driving NKG2D and NKG2D ligand expression, respectively. Blocking NKG2D reduced degranulation by CD8 T cells in a subset of patients. Additionally, our transcriptional analysis of patients’ lesions found that patients who failed the first round of treatment exhibited higher expression of KLRK1 , the gene coding for NKG2D, than those who responded to treatment. These findings suggest that NKG2D may be a promising therapeutic target for ameliorating disease severity in cutaneous leishmaniasis caused by L . braziliensis infection.

Bacterial meningitis is an increasingly rare disease that carries significant morbidity and mortality. We describe the case of a 38-year-old male with a past medical history of pituitary macroadenoma with prior endonasal surgeries on prednisone therapy daily for resultant hypopituitarism and juvenile myoclonic epilepsy on lamotrigine daily who was transferred to an academic tertiary emergency department due to concern for developing pituitary apoplexy. At the outside emergency department, the patient presented complaining of sudden onset severe headache. CT scan demonstrated residual pituitary mass but no additional findings. On arrival to our emergency department, the patient was altered and newly febrile. Physical exam was notable for the patient moving all extremities and opening eyes spontaneously but unable to follow commands with a positive Kernig's sign. Broad spectrum antibiotics, antivirals, and stress dosed steroids were started due to concern for meningitis, and Neurology and Neurosurgery were consulted. Repeat CT was obtained prior to lumbar puncture (LP). LP demonstrated bacterial meningitis, which later speciated to Streptococcus salivarius. The patient was admitted to the medical ICU and discharged with full neurologic recovery on hospital day 13. This case demonstrates the variable presentation of bacterial meningitis as the patient was not initially febrile or altered. Emergency physicians index of suspicion for meningitis should be increased with risk factors such as immunosuppression and history of transsphenoidal surgery, as in our patient. Our case is a unique case of Streptococcus salivarius meningitis that has been previously associated with primarily iatrogenic etiologies.

The indications for ECMO were respiratory failure (63%), cardiac failure (29%), and as a last resort in cardiopulmonary resuscitation (8%). The rate of extracorporeal cardiopulmonary resuscitation (CPR) is also increasing. Case Report A 45-year-old man suffered a cardiac arrest at home followed by recurrent ventricular fibrillation requiring cumulatively more than 60 min of CPR. During hypothermic cardiopulmonary bypass, an arterial pH of approximately 7.40 and PaCO2 of 40 mmHg is maintained and corrected to the patient’s actual temperature. Because of the alkaline shift in pH during cooling due to increased CO2 solubility, CO2 is added to the sweep gas

Innate lymphoid cells (ILCs) comprise a heterogeneous population of immune cells that maintain barrier function and can initiate a protective or pathological immune response upon infection. Here we show the involvement of IL-17A-producing ILCs in microbiota-driven immunopathology in cutaneous leishmaniasis. IL-17A-producing ILCs were RORγt + and were enriched in Leishmania major infected skin, and topical colonization with Staphylococcus epidermidis before L . major infection exacerbated the skin inflammatory responses and IL-17A-producing RORγt + ILC accumulation without impacting type 1 immune responses. IL-17A responses in ILCs were directed by Batf3 dependent CD103 + dendritic cells and IL-23. Moreover, experiments using Rag1 -/- mice established that IL-17A + ILCs were sufficient in driving the inflammatory responses as depletion of ILCs or neutralization of IL-17A diminished the microbiota mediated immunopathology. Taken together, this study indicates that the skin microbiota promotes RORγt + IL-17A-producing ILCs, which augment the skin inflammation in cutaneous leishmaniasis.