Natural killer (NK) cells are a subset of immune effectors that directly bind and kill fungi via a perforin-dependent mechanism. The receptor mediating this activity and its potential role in disease remain unknown. Using an unbiased approach, we determined that NKp30 is responsible for recognition and killing of the fungal pathogens Cryptococcus and Candida. NKp30 was required for NK cell-fungal conjugate formation, phosphatidylinositol 3-kinase (PI3K) signaling, and perforin release. Because fungal infections are a leading cause of death in AIDS patients, we examined NKp30 expression in HIV-infected patients. NK cells from these patients had diminished NKp30 expression, defective perforin release, and blunted microbicidal activity. Surprisingly, interleukin-12 (IL-12) restored NKp30 expression and fungal killing. Thus, the NKp30 receptor plays a critical role in NK cell antifungal cytotoxicity, and diminished expression of NKp30 is responsible for defective antifungal activity of NK cells from HIV-infected patients, which can be corrected with IL-12.

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory condition of the upper airways. Optimal management is unclear. Objective: We compared the effects of mAbs and aspirin desensitization (ASA-D) for treatment of CRSwNP. Methods: We searched the Medline, Embase, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, US Food and Drug Administration, and the European Medicines Agency databases from inception to August 4, 2021, for randomized controlled trials comparing the effects of mAbs and ASA-D for CRSwNP. We conducted network meta-analysis of sinusitis symptoms, heath-related quality of life, rescue oral corticosteroids and surgery, endoscopic and radiologic scores, and adverse events. We used the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach to assess certainty of evidence. PROSPERO CRD42020177334. Results: Twenty-nine randomized controlled trials evaluating 8 treatments (n 5 3461) were included in the network metaanalysis. Compared to placebo, moderate to high certainty evidence showed that health-related quality of life (SNOT-22) improved with dupilumab (mean difference [MD] 219.91 [95%

BackgroundAllergic diseases such as asthma and allergic rhinitis constitute a significant burden of disease among women of childbearing age and those who are pregnant. Adequately managing these conditions is paramount in reducing negative fetal outcomes as well as maternal complications during pregnancy. However, the potential for harm to both the mother and fetus demands carefully balancing efficacy and safety of treatment. Allergen immunotherapy (AIT) has emerged as a relatively safe and efficacious mode of therapy in both children and adults. AIT has also been considered for use during pregnancy.MethodsA review of the literature was conducted for data regarding the safety of initiation and continuation of AIT during pregnancy as well as the effect of AIT on the development of atopy in offspring. MEDLINE and the Cochrane Library were searched for clinical trials, randomized control trials, observational studies and journal articles in English using the terms "Pregnancy" and "Immunotherapy" from 1900 to present. This yielded 4 studies (totaling 422 pregnancies receiving AIT) investigating the continuation of AIT in pregnancy, 2 (totaling 31 pregnancies receiving AIT) evaluating AIT initiation during pregnancy and 5 observing the effect of AIT on atopy in offspring.ResultsNo significant difference was found in the incidence of prematurity, hypertension (HTN)/proteinuria, congenital malformations or perinatal deaths between the women continued on AIT (both subcutaneous (SC) IT and sublingual (SL) IT to inhalant allergens as well as venom IT) during pregnancy and controls. Similarly, there was no significant difference in maternal or fetal complications between pregnant women initiated on AIT and controls. Among the few pregnant women (10/453 pregnancies) who experienced generalized reactions while receiving AIT, none were found to have fetal complications. Neither SCIT nor SLIT during pregnancy altered the risk of developing atopic disease in offspring.ConclusionsBased on these data, the continuation of AIT during pregnancy appears safe. Furthermore, the few data available suggest that the initiation of AIT during pregnancy might also be safe, however, more data is required for a definitive conclusion. Lastly, available studies do not show a convincing reduction in the development of atopy in offspring from the administration of AIT during pregnancy.

Cryptococcus gattii and Cryptococcus neoformans are encapsulated yeasts that can produce a solid tumor-like mass or cryptococcoma. Analogous to malignant tumors, the microenvironment deep within a cryptococcoma is acidic, which presents unique challenges to host defense. Analogous to malignant cells, NK cells kill Cryptococcus. Thus, as in tumor defense, NK cells must kill yeast cells across a gradient from physiologic pH to less than 6 in the center of the cryptococcoma. As acidic pH inhibits anti-tumor activities of NK cells, we sought to determine if there was a similar reduction in the anticryptococcal activity of NK cells. Surprisingly, we found that both primary human NK cells and the human NK cell line, YT, have preserved or even enhanced killing of Cryptococcus in acidic, compared to physiological, pH. Studies to explore the mechanism of enhanced killing revealed that acidic pH does not increase the effector to target ratio, binding of cytolytic cells to Cryptococcus, or the active perforin content in effector cells. By contrast, perforin degranulation was greater at acidic pH, and increased degranulation was preceded by enhanced ERK1/2 phosphorylation, which is essential for killing. Moreover, using a replication defective ras1 knockout strain of Cryptococcus increased degranulation occurred during more rapid replication of the organisms. Finally, NK cells were found intimately associated with C. gattii within the cryptococcoma of a fatal infection. These results suggest that NK cells have amplified signaling, degranulation, and greater killing at low pH and when the organisms are replicating quickly, which would help maintain microbicidal host defense despite an acidic microenvironment.

Natural killer (NK) cells directly recognize and kill fungi, such as the pathogenic fungus Cryptococcus neoformans, via cytolytic mechanisms. However, the precise signaling pathways governing this NK cell microbicidal activity and the implications for fungal recognition are still unknown. Previously, it was reported that NK cell anticryptococcal activity is mediated through a conserved phosphatidylinositol 3-kinase-extracellular signal-regulated kinase 1/2 (PI3K-ERK1/2) pathway. Using YT (a human NK-like cell line) and primary human NK cells, we sought to identify the upstream, receptor-proximal signaling elements that led to fungal cytolysis. We demonstrate that Src family kinases were activated in response to C. neoformans. Furthermore, pharmacologic inhibition with an Src kinase inhibitor blocked C. neoformans-induced downstream activation of PI3K and ERK1/2 and abrogated cryptococcal killing. At the same time, the inhibitor disrupted the polarization of perforin-containing granules toward the NK cell-cryptococcal synapse but had no effect on conjugate formation between the organism and the NK cell. Finally, small interfering RNA (siRNA) double (but not single) knockdown of two Src family kinases, Fyn and Lyn, blocked cryptococcal killing. Together these data demonstrate a mechanism whereby the Src family kinases, Fyn and Lyn, redundantly mediate anticryptococcal activity through the activation of PI3K and ERK1/2, which in turn facilitates killing by inducing the polarization of perforin-containing granules to the NK cell-cryptococcal synapse.