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1.
Artigo em Inglês | MEDLINE | ID: mdl-31617907

RESUMO

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are expected to be widely adopted globally, requiring surveillance of resistance emergence and transmission. OBJECTIVES: We therefore sought to develop a standardized list of INSTI-resistance mutations suitable for the surveillance of transmitted INSTI resistance. METHODS: To characterize the suitability of the INSTI-resistance mutations for transmitted HIV-1 drug resistance (TDR) surveillance, we classified them according to their presence on published expert lists, conservation in INSTI-naive persons, frequency in INSTI-treated persons and contribution to reduced in vitro susceptibility. Mutation prevalences were determined using integrase sequences from 17 302 INSTI-naive and 2450 INSTI-treated persons; 53.3% of the INSTI-naive sequences and 20.0% of INSTI-treated sequences were from non-B subtypes. Approximately 10% of sequences were from persons who received dolutegravir alone or a first-generation INSTI followed by dolutegravir. RESULTS: Fifty-nine previously recognized (or established) INSTI-resistance mutations were present on one or more of four published expert lists. They were classified into three main non-overlapping groups: 29 relatively common non-polymorphic mutations, occurring in five or more individuals and significantly selected by INSTI treatment; 8 polymorphic mutations; and 22 rare mutations. Among the 29 relatively common INSTI-selected mutations, 24 emerged as candidates for inclusion on a list of INSTI surveillance drug-resistance mutations: T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, N155H, S230R and R263K. CONCLUSIONS: A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.

2.
Proc Natl Acad Sci U S A ; 116(42): 20881-20885, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31570618

RESUMO

Optimization algorithms and Monte Carlo sampling algorithms have provided the computational foundations for the rapid growth in applications of statistical machine learning in recent years. There is, however, limited theoretical understanding of the relationships between these 2 kinds of methodology, and limited understanding of relative strengths and weaknesses. Moreover, existing results have been obtained primarily in the setting of convex functions (for optimization) and log-concave functions (for sampling). In this setting, where local properties determine global properties, optimization algorithms are unsurprisingly more efficient computationally than sampling algorithms. We instead examine a class of nonconvex objective functions that arise in mixture modeling and multistable systems. In this nonconvex setting, we find that the computational complexity of sampling algorithms scales linearly with the model dimension while that of optimization algorithms scales exponentially.

3.
J Immunol ; 203(9): 2451-2458, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31562208

RESUMO

Granuloma formation is a hallmark of several infectious diseases, including those caused by Mycobacterium sp These structures are composed of accumulations of inflammatory cells, and it has been shown that cytokines such as IFN-γ and TNF-α are required for granuloma assembly during M. avium infections in mice. Macrophages (MΦs) insensitive to IFN-γ (MIIG) mice have MΦs, monocytes, and dendritic cells that are unresponsive to IFN-γ. We observed that although IFN-γ-/- mice present an exacerbated infection, the same is not true for MIIG animals, where the same levels of protection as the wild-type animals were observed in the liver and partial protection in the spleen. Unlike IFN-γ-/- mice, MIIG mice still develop well-defined granulomas, suggesting that IFN-γ-mediated MΦ activation is not required for granuloma assembly. This work also shows that MIIG animals exhibit increased cell recruitment with higher CD4+ T cells numbers as well as increased IFN-γ and TNF-α expression, suggesting that TNF-α may have a role in protection and may compensate the lack of MΦ response to IFN-γ in the MIIG model. TNF-α-deficient MIIG mice (MIIG.TNF-α-/-) exhibited increased bacterial burdens when compared with MIIG mice. These results suggest that in the absence of IFN-γ signaling in MΦs, TNF-α has a protective role against M. avium.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31442594

RESUMO

We have previously reported that a peripheral blood absolute CD38brightCD8+ effector memory T cell (TEM) population expansion of >35 cells/µL predicts the development of acute graft-versus-host disease (GVHD). We hypothesized that these T cells are activated, proliferating, and cytotoxic trafficking cells that are not a response to viral reactivation and may be involved in acute GVHD. We characterized peripheral blood T cell populations at the time of maximum CD38brightCD8+ TEM expansion in patients from our originally reported pediatric allogeneic hematopoietic cell transplantation recipient cohort. Samples were incubated with fluorochrome-conjugated antibodies directed against CD3, CD8, CD38, HLA-DR (T cell activation), Ki-67 (T cell proliferation), granzyme B (marker of cytotoxic T cells), CLA (skin trafficking), CCR5 (visceral trafficking), and CXCR6 (liver trafficking). We also incubated samples with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) peptide pools and measured IFN-γ production by flow cytometry and performed EBV and CMV tetramer staining. Higher median proportions of cell expression of HLA-DR, Ki-67, granzyme B, CLA, CCR5, and CXCR6 were observed for CD38brightCD8+ T cells compared with CD38nonbrightCD8+ T cells in patients with acute GVHD (P < .05) but not in patients without acute GVHD (P not significant). No IFN-γ production was observed after incubation with CMV and EBV peptide pools. EBV-specific tetramer populations of 6.85% and 3.17% were detected in 2 patients with acute GVHD, whereas a CMV-specific tetramer population of 3.77% was detected in 1 patient with acute GVHD. No EBV- or CMV-specific tetramer populations were detected in any patient without acute GVHD. We conclude that CD38brightCD8+ T cells associated with the development of acute GVHD are activated, proliferating, and cytotoxic trafficking cells that do not appear to respond to CMV or EBV reactivation. Further studies are needed to determine whether these cells are directly involved in acute GVHD pathogenesis.

6.
J Clin Invest ; 130: 4451-4463, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31408438

RESUMO

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype. METHODS: We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus. RESULTS: Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months. CONCLUSION: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904). FUNDING: Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.

7.
Transplantation ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31415033

RESUMO

BACKGROUND: Renal allograft rejection is more frequent under belatacept-based, compared to tacrolimus-based, immunosuppression. We studied kidney transplant recipients experiencing rejection under belatacept-based early corticosteroid withdrawal following T cell depleting induction in a recent randomized trial (BEST Trial, clinicaltrials.gov #NCT01729494) to determine mechanisms of rejection and treatment. METHODS: Peripheral mononuclear cells, serum creatinine levels, and renal biopsies were collected from 8 patients undergoing belatacept-refractory rejection. We used flow cytometry, histology and immunofluorescence to characterize CD8 effector memory T cell (TEM) populations in the periphery and graft before and after mammalian target of rapamycin (mTOR) inhibition. RESULTS: Here, we found that patients with belatacept-refractory rejection (BRR) did not respond to standard antirejection therapy and had a substantial increase in alloreactive CD8 T cells with a CD28/DR/CD38/CD45RO TEM. These cells had increased activation of the mTOR pathway, as assessed by phosphorylated ribosomal protein S6 (p-RPS6) expression. Notably, everolimus (an mTOR inhibitor) treatment of patients with BRR halted the in vivo proliferation of TEM cells, their ex vivo alloreactivity, and resulted in their significant reduction in the peripheral blood. The frequency of circulating FoxP3 regulatory T cells was not altered. Importantly, everolimus led to rapid resolution of rejection as confirmed by histology. CONCLUSIONS: Thus, while prior work has shown that concomitant belatacept + mTOR inhibitor therapy is effective for maintenance immunosuppression, our preliminary data suggest that everolimus may provide an available means for effecting "rescue" therapy for rejections occurring under belatacept that are refractory to traditional antirejection therapy with corticosteroids and polyclonal antilymphocyte globulin.

8.
Pediatr Blood Cancer ; 66(11): e27929, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31339233

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.

9.
AIDS ; 33(11): 1797-1799, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31149946

RESUMO

: Use of dolutegravir-based first-line antiretroviral therapy (ART) in response to rising levels of pretreatment HIV drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) may be limited, given safety concerns for birth defects in women of child-bearing potential. Pooled data from 11 nationally representative surveys show that NNRTI PDR in women is nearly twice that in men, exceeding 10% in 8 of 11 countries monitored, suggesting the urgent need for a non-NNRTI-based ART regimen in this population.

11.
Front Immunol ; 10: 998, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156616

RESUMO

CTLA-4 is essential for immune tolerance. Heterozygous CTLA4 mutations cause immune dysregulation evident in defective regulatory T cells with low levels of CTLA-4 expression. Biallelic mutations in LRBA also result in immune dysregulation with low levels of CTLA-4 and clinical presentation indistinguishable from CTLA-4 haploinsufficiency. CTLA-4 has become an immunotherapy target whereby its blockade with a monoclonal antibody has resulted in improved survival in advanced melanoma patients, amongst other malignancies. However, this therapeutic manipulation can result in autoimmune/inflammatory complications reminiscent of those seen in genetic defects affecting the CTLA-4 pathway. Despite efforts made to understand and establish disease genotype/phenotype correlations in CTLA-4-haploinsufficiency and LRBA-deficiency, such relationships remain elusive. There is currently no specific immunological marker to assess the degree of CTLA-4 pathway disruption or its relationship with clinical manifestations. Here we compare three different patient groups with disturbances in the CTLA-4 pathway-CTLA-4-haploinsufficiency, LRBA-deficiency, and ipilimumab-treated melanoma patients. Assessment of CTLA4 mRNA expression in these patient groups demonstrated an inverse correlation between the CTLA4 message and degree of CTLA-4 pathway disruption. CTLA4 mRNA levels from melanoma patients under therapeutic CTLA-4 blockade (ipilimumab) were increased compared to patients with either CTLA4 or LRBA mutations that were clinically stable with abatacept treatment. In summary, we show that increased CTLA4 mRNA levels correlate with the degree of CTLA-4 pathway disruption, suggesting that CTLA4 mRNA levels may be a quantifiable surrogate for altered CTLA-4 expression.

12.
PLoS One ; 14(5): e0214251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31059507

RESUMO

OBJECTIVES: The concurrent implementation of targeted (tPITC) and blanket provider-initiated testing and counselling (bPITC) is recommended by the World Health Organization (WHO) for HIV case-finding in generalized HIV epidemics. This study assessed the effectiveness of this intervention compared to symptom-based diagnostic HIV testing (DHT) in terms of HIV testing uptake, case detection and antiretroviral therapy (ART) enrollment among children and adolescents in Cameroon, where estimated HIV prevalence is relatively low at 3.7%. METHODS: In three hospitals where DHT was the standard practice before, tPITC and bPITC were implemented by inviting HIV-positive parents in care at the ART clinics to have their biological children (6 weeks-19 years) tested for HIV (tPITC). Concurrently, at the outpatient departments, similarly-age children/adolescents were systematically offered HIV testing via accompanying parents/guardians. The mean monthly number of children tested for HIV, identified HIV-positive and ART-enrolled were used to compare the outcomes of different HIV testing strategies before and after the intervention. RESULTS: In comparing DHT to bPITC, there was a significant increase in the mean monthly number of children/adolescents tested for HIV (223.0 vs 348.3, p = 0.0073), but with no significant increase in the mean monthly number of children/adolescents: testing HIV-positive (10.5 vs 9.7, p = 0.7574) and ART- enrolled (7.3 vs 6.3, p = 0.5819). In comparing DHT to tPITC, there was no significant difference in the mean monthly number of children/adolescents: tested for HIV (223 vs 193.8, p = 0.4648); tested HIV-positive (10.5 vs 10.6, p = 0.9544), and ART-enrolled (7.3 vs 5.8, p = 0.4672). When comparing DHT versus bPITC+tPITC, there was a significant increase in the mean monthly number of children/adolescents: tested for HIV (223.0 to 542.2, p<0.0001), testing HIV-positive (10.5 vs 20.3, p = 0.0256), and ART-enrolled (7.3 vs 12.2, p = 0.0388). CONCLUSIONS: These findings suggest that concurrent implementation of bPITC+tPITC was more effective compared to DHT in terms of HIV testing uptake, case detection and ART enrolment. However, considering that DHT and bPITC had comparable outcomes with regards to case detection and ART enrolment, bPITC+tPITC may not be efficient. Thus, this finding does not support concurrent bPITC+tPITC implementation as recommended by WHO. Rather, continued DHT+tPITC could effectively and efficiently accelerate HIV case detection and ART coverage among children and adolescents in Cameroon and similar low-prevalence context.

13.
Blood ; 133(23): 2465-2477, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-30992265

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

14.
Am J Health Promot ; 33(6): 869-875, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30773023

RESUMO

PURPOSE: To characterize plant-based dietary practices and examine their relationship with body mass index (BMI) in Hispanic/Latino Seventh-day Adventists (SDA). DESIGN: Cross-sectional analyses of data among Hispanics/Latinos in the Adventist Health Study-2 (AHS-2). SETTING: The AHS-2 is a cohort of SDA adults (n = 96 592) in North America. PARTICIPANTS: A total of 3475 Hispanics/Latinos who provided demographic, dietary, anthropometric, and lifestyle data at enrollment. MEASURES: Plant-based dietary practices were determined from food frequency questionnaire; BMI, demographic, and lifestyle data were assessed by questionnaire. ANALYSIS: In linear regression analysis, plant-based diets were modeled as dummy variables with nonvegetarian as the referent group and log(BMI) as the outcome adjusted for age, sex, education, exercise, nativity, alcohol use, smoking, and energy intake. RESULTS: We identified 202 vegans, 664 vegetarians, 409 pesco-vegetarians, 227 semi-vegetarians, and 1973 nonvegetarians. Compared to the nonvegetarian referent (BMI = 27.50), estimated BMI were lower among vegans (23.58, P < .0001), vegetarians (25.24, P < .0001), pesco-vegetarians (26.36, P = .0002), and semi-vegetarians (26.69, P = .130). Other factors associated with lower BMI were being female (P = .001), nativity (Mexico, P = .002; South America, P < .0001; Caribbean, P = .004), having a college degree or higher (P = .01), exercise (P < .0001), and never smoked (P = .0006). CONCLUSION: Hispanic/Latino SDAs who consumed plant-based diets had lower BMI than nonvegetarians. The application of a plant-based diet as practiced by the Hispanic/Latino Adventists in this population may have public health impact on US Hispanic/Latinos.

15.
Antivir Ther ; 24(3): 203-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30741163

RESUMO

BACKGROUND: Sentinel surveillance of transmitted HIV drug resistance (TDR) among recently infected populations within a country was recommended by the World Health Organization from 2004 to 2015. METHODS: Serum specimens collected as part of the 2010, 2011 and 2012 National Antenatal Sentinel HIV Prevalence Surveys were used to estimate provincial and national TDR prevalence in South Africa. RESULTS: Moderate (5-15%) levels of transmitted non-nucleoside reverse transcriptase inhibitor (NNRTI) drug class resistance were detected in three of five provinces surveyed in 2010 and 2011 (Eastern Cape, Free State and KwaZulu-Natal). Inclusion of all nine of South Africa's provinces in the 2012 survey enabled calculation of a national TDR point prevalence estimate: TDR to the NNRTI drug class was 5.4% (95% CI 3.7, 7.8%), with K103N and V106M being the most frequently detected mutations. TDR estimates for the nucleoside reverse transcriptase inhibitor (NRTI) drug class were 1.1% (95% CI 0.5, 2.4%) and 0.6% (95% CI 0.1, 1.6%) for protease inhibitors (PI). CONCLUSIONS: These data provide national TDR estimates for South Africa in 2012 and indicate that levels of TDR were low to moderate for the NNRTI drug class and low for NRTIs and PIs in the population surveyed.

17.
ACS Synth Biol ; 8(3): 532-547, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30694661

RESUMO

Type III secretion (T3S) systems are essential pathogenicity factors of most Gram-negative bacteria and translocate effector proteins into plant or animal cells. T3S systems can, therefore, be used as tools for protein delivery into eukaryotic cells, for instance after transfer of the T3S gene cluster into nonpathogenic recipient strains. Here, we report the modular cloning of the T3S gene cluster from the plant-pathogenic bacterium Xanthomonas euvesicatoria. The resulting multigene construct encoded a functional T3S system and delivered effector proteins into plant cells. The modular design of the T3S gene cluster allowed the efficient replacement and rearrangement of single genes or operons and the insertion of reporter genes for functional studies. In the present study, we used the modular T3S system to analyze the assembly of a fluorescent fusion of the predicted cytoplasmic ring protein HrcQ. Our studies demonstrate the use of the modular T3S gene cluster for functional analyses and mutant approaches in X. euvesicatoria. A potential application of the modular T3S system as protein delivery tool is discussed.

18.
AIDS Care ; : 1-11, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30497271

RESUMO

Mobile phones are increasingly being used to support health activities, including the care and management of people living with HIV/AIDS. Short message service (SMS) has been explored as a means to optimize and support behaviour change. However, there is minimal guidance on messaging content development. The purpose of this review was to inform the content of SMS messages for mobile health (mHealth) initiatives designed to support anti-retroviral therapy adherence and clinic appointment keeping in resource-limited settings. PubMed, OvidMedline, Google Scholar, K4Health's mHealth Evidence database, the mHealth Working Group project resource, and Health COMpass were searched. A request to online communities for recommendations on message content was also made. 1010 unique sources were identified, of which 51 were included. The information was organized into three categories: pre-message development, message development, and security and privacy. Fifteen of the publications explicitly provided their message content. Important lessons when developing the content of SMS were: (1) conducting formative research; (2) grounding content in behaviour change theory; and (3) reviewing proposed content with experts. Best practices exist for developing message content for behaviour change. Efforts should be continued to apply lessons learned from the existing literature to inform mHealth initiatives supporting HIV/AIDS care and treatment.

19.
Nat Methods ; 15(12): 1053-1058, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30504886

RESUMO

Single-cell transcriptome measurements can reveal unexplored biological diversity, but they suffer from technical noise and bias that must be modeled to account for the resulting uncertainty in downstream analyses. Here we introduce single-cell variational inference (scVI), a ready-to-use scalable framework for the probabilistic representation and analysis of gene expression in single cells ( https://github.com/YosefLab/scVI ). scVI uses stochastic optimization and deep neural networks to aggregate information across similar cells and genes and to approximate the distributions that underlie observed expression values, while accounting for batch effects and limited sensitivity. We used scVI for a range of fundamental analysis tasks including batch correction, visualization, clustering, and differential expression, and achieved high accuracy for each task.

20.
Front Immunol ; 9: 2131, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30283457

RESUMO

Invasive fungal infections, including Pneumocystis Pneumonia (PcP), remain frequent life-threatening conditions of patients with adaptive immune defects. While innate immunity helps control pathogen growth early during infection, it is typically not sufficient for complete protection against Pneumocystis and other human fungal pathogens. Alveolar macrophages (AM) possess pattern recognition molecules capable of recognizing antigenic and structural determinants of Pneumocystis. However, this pathogen effectively evades innate immunity to infect both immunocompetent and immunosuppressed hosts, albeit with differing outcomes. During our studies of mouse models of PcP, the FVB/N strain was identified as unique because of its ability to mount a protective innate immune response against Pneumocystis infection. In contrast to other immunocompetent strains, which become transiently infected prior to the onset of adaptive immunity, FVB/N mice rapidly eradicated Pneumocystis before an adaptive immune response was triggered. Furthermore, FVB/N mice remained highly resistant to infection even in the absence of functional T cells. The effector mechanism of innate protection required the action of functional alveolar macrophages, and the adoptive transfer of resistant FVB/N AMs, but not susceptible CB.17 AMs, conferred protection to immunodeficient mice. Macrophage IFNγ receptor signaling was not required for innate resistance, and FVB/N macrophages were found to display markers of alternative activation. IFNγ reprogrammed resistant FVB/N macrophages to a permissive M1 biased phenotype through a mechanism that required direct activation of the macrophage IFNγR. These results demonstrate that appropriately programmed macrophages provide protective innate immunity against this opportunistic fungal pathogen, and suggest that modulating macrophage function may represent a feasible therapeutic strategy to enhance antifungal host defense. The identification of resistant and susceptible macrophages provides a novel platform to study not only the mechanisms of macrophage-mediated antifungal defense, but also the mechanisms by which Pneumocystis evades innate immunity.

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