Early alveolar macrophage response and IL-1R-dependent T cell priming determine transmissibility of Mycobacterium tuberculosis strains.

Mechanisms underlying variability in transmission of Mycobacterium tuberculosis strains remain undefined. By characterizing high and low transmission strains of M.tuberculosis in mice, we show here that high transmission M.tuberculosis strain induce rapid IL-1R-dependent alveolar macrophage migration from the alveolar space into the interstitium and that this action is key to subsequent temporal events of early dissemination of bacteria to the lymph nodes, Th1 priming, granulomatous response and bacterial control. In contrast, IL-1R-dependent alveolar macrophage migration and early dissemination of bacteria to lymph nodes is significantly impeded in infection with low transmission M.tuberculosis strain; these events promote the development of Th17 immunity, fostering neutrophilic inflammation and increased bacterial replication. Our results suggest that by inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M.tuberculosis strain is poised for greater transmissibility. These findings implicate bacterial heterogeneity as an important modifier of TB disease manifestations and transmission.

Anti-SARS-CoV-2 antibody immunoreactivity profiles during COVID-19 recurrence

ABSTRACT Background: This study aimed to evaluate IgG and IgM levels in COVID-19 recurrence. Methods: The serum antibody levels and clinical data from 73 healthcare workers with SARS-CoV-2 divided into seroconverted (n=51) and non-seroconverted (n=22) groups were assessed. The presence of specific anti-nucleocapsid (anti-N) IgM and IgG for SARS-CoV-2 was evaluated. IgG antibodies to the SARS-CoV-2 spike receptor-binding domain were used to confirm non-seroconversion in all negative anti-N. Results: Four recurrent cases displayed mild symptoms and were non-seroconverted until the recurrence of symptoms. Conclusions: Undetectable anti-nucleocapsid IgM and IgG levels may be correlated with symptomatic COVID-19 recurrence.

Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8+ T cells in human cutaneous leishmaniasis.

Cytotoxic activity mediated by CD8+ T cells is the main signature of the immunopathogenesis of cutaneous leishmaniasis (CL). Here, we performed a broad evaluation of natural killer (NK) cell phenotypic and functional features during cutaneous leishmaniasis. We demonstrate for the first time that CL patients present the accumulation of circulating NK cells with multiple features of replicative senescence including low proliferative capacity and shorter telomeres, elevated expression of CD57, KLRG1 but diminished CD27 stimulatory receptor expression. Moreover, they exhibited higher cytotoxic and inflammatory potential than age-matched controls. The accumulation of circulating senescent NK cells (CD56dim  CD57bright ) correlated positively with skin lesion size in the same patients, suggesting that they, like circulating senescent CD8+ T cells, may contribute to the immunopathology of CL. However, this senescent population had lower cutaneous lymphocyte antigen expression and so had diminished skin-homing potential compared with total or senescent CD8+ T cells. This was confirmed in CL skin lesions where we found a predominance of CD8+ T cells (both senescent and non-senescent) that correlated with the severity of the disease. Although there was also a correlation between the proportions of senescent NK cells (CD56+  CD57+ ) in the skin and lesion size, this was less evident. Collectively our results demonstrate first-hand that senescent cytotoxic cells may mediate skin pathology during human cutaneous leishmaniasis. However, as senescent cytotoxic CD8+ T cells predominate in the skin lesions, they may have a greater role than NK cells in mediating the non-specific skin damage in CL.

Transmission phenotype of Mycobacterium tuberculosis strains is mechanistically linked to induction of distinct pulmonary pathology.

In a study of household contacts (HHC), households were categorized into High (HT) and Low (LT) transmission groups based on the proportion of HHC with a positive tuberculin skin test. The Mycobacterium tuberculosis (Mtb) strains from HT and LT index cases of the households were designated Mtb-HT and Mtb-LT, respectively. We found that C3HeB/FeJ mice infected with Mtb-LT strains exhibited significantly higher bacterial burden compared to Mtb-HT strains and also developed diffused inflammatory lung pathology. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. None of the Mtb-HT infected animals developed diffused inflammatory lung pathology. A link was observed between increased in vitro replication of Mtb-LT strains and their ability to induce significantly high lipid droplet formation in macrophages. These results support that distinct early interactions of Mtb-HT and Mtb-LT strains with macrophages and subsequent differential trajectories in pathological disease may be the mechanism underlying their transmission potential.

Dyslipidemia and fasting glucose impairment among HIV patients three years after the first antiretroviral regimen in a Brazilian AIDS outpatient clinic

OBJECTIVE: To evaluate the cumulative incidence of dyslipidemia and fasting glucose impairment three years after initiating the first antiretroviral (ART) regimen and the association with the type of ART regimen in an AIDS outpatient clinic in Brazil. METHODS: Retrospective cohort of HIV-1 infected patients attending an outpatient HIV clinic in Vitoria, Brazil, between January/2010 and May/2011. Data, including blood pressure, dyslipidemia (high total cholesterol and low HDL-C), fasting glucose, and cardiovascular risk by Framingham Risk Score were abstracted from medical records from clinic visits six months prior and three years after starting ART. We assessed independent associated factors for dyslipidemia using multiple logistic regression. RESULTS: Four hundred and ninety-eight patients on ART were studied. Median age was 45 years (interquartile range (IQR): 37-52), and median time since HIV diagnosis was 7.7 years (IQR: 3.8-10.0). The proportion of patients with dyslipidemia was 22.3% (95% CI: 18.6-25.9%) 36 months after ART initiation. Triglycerides levels >150 mg/dL (55.2% vs. 25.4%, p = 0.021) and high fasting glucose (5.8% vs. 2.3%, p = 0.034) were diagnosed more frequently after ART use when compared to baseline values. Multiple logistic regression analysis has shown dyslipidemia to be associated with lopinavir/r use [OR = 1.74 (95% CI: 1.12-2.86)]. CONCLUSION: These data show high chance of dyslipidemia after initiation of ART. Long-term follow-up will help identify the impact of ART on cardiovascular risk.

Low bone mass prevalence, therapy type, and clinical risk factors in an HIV-infected Brazilian population.

Low bone mineral density (BMD) has been described in human immunodeficiency virus (HIV)-infected patients, but data on associated factors are still unclear, and to our knowledge, no reports are available in Brazil. Our goal was to evaluate BMD in HIV patients attending an outpatient clinic in Vitoria, Brazil. A sectional study was performed in 300 HIV-infected patients to measure BMD by dual-energy X-ray absorptiometry (DXA). Age, gender, anthropometric parameters, nadir and current CD4 cell count, HIV viral load, smoking habit, and current antiretroviral therapy (ART) associations were investigated by multivariable analysis. Based on World Health Organization T-score ranges, low BMD (T-score <-1.0 standard deviation [SD] in postmenopausal women and men aged 50 and older or Z-score <- 2.0 SD in premenopausal women and men below the age of 50) was detected in 54.7% (95% confidence interval: 49.1-60.3%) of the 300 enrolled patients. The observed median age was 46 yr (interquartile range: 39-52), 58% were male, 88.5% were on ART, and 21.4% smoked. The following factors were identified, by multiple logistic modeling, as being independently associated with low BMD: (1) male gender (4.6 [1.28-16.39]), (2) body mass index lower than 25 kg/m(2) (2.9 [1.31-6.49]), (3) menopause (13.4 [2.53-71.12]), and (4) HIV-1 undetectable viral load (7.9 [1.96-32.25]). Conversely, zidovudine (0.2 [0.04-0.85]) and nevirapine (0.1 [0.02-0.38]) use were inversely associated with low BMD. Low BMD was frequently found in our cohort of about 300 Brazilian HIV-infected subjects. This study supports the need for periodic DXA testing in HIV outpatient clinics.

Presence of Borrelia burgdorferi "Sensu Lato" in patients with morphea from the Amazonic region in Brazil.

BACKGROUND: In the present study, Borrelia spirochetes were found in four (26.6%) out of 15 patients with Atrophoderma of Pasini and Pierini (IAPP) and lichen sclerosis et atrophicans (LSA) from the Brazilian Amazon Region. MATERIAL AND METHODS: Borreliosis was investigated by immunohistochemistry and focus floating microscopy for Borrelia burgdorferi in skin biopsy samples from 15 patients with both clinical and histopathology evidences compatible with Morphea, LSA, and IAPP. RESULTS: Spirochetes were detected by specific immunohistochemistry and focus floating microscopy for B. burgdorferi in samples from three patients. A limitation of our study was the fact that we were not able to isolate and culture these organisms. CONCLUSION: Our data confirm the presence of borreliosis cases in the Amazon.

Síndrome de restauração imune associada à histoplasmose / Histoplasmosis-associated immune reconstitution inflammatory syndrome

Paciente masculino, 27 anos, portador de HIV, com quadro de histoplasmose cutânea disseminada. Terapia antirretroviral oral e anfotericina B por via EV (dose total acumulada 0,5g) foram introduzidas, verificando-se rápida cicatrização das lesões após duas semanas. A anfotericina B foi substituída por itraconazol (200mg/dia). O paciente interrompeu voluntariamente os tratamentos. A terapia antirretroviral foi reintroduzida, havendo aumento da contagem de células T CD4-positivas (No restante do texto, a autora usa o símbolo "+" (T CD4+) ao invés da palavra "positiva". O que fazer neste caso? Seguimos o padrão do restante do texto ou acatamos essa opção da autora no resumo?!). Neste momento, diagnosticou-se histoplasmose ganglionar. O aumento da contagem de células T CD4-positivas (de novo aqui), associado à redução da carga viral a níveis inferiores ao limite de detecção após a reintrodução da terapia antirretroviral, sugere que essa piora clínica paradoxal seja uma síndrome de restauração imune.

A 27-year-old HIV-positive male patient with disseminated cutaneous histoplasmosis was treated with both HAART and amphotericin B (total accumulated dose of 0.5g). Amphotericin B was later replaced with itraconazole (200mg/day). Two months after therapy had been started and the cutaneous lesions had healed, the patient interrupted both treatments voluntarily and his health deteriorated. HAART was then re-introduced and CD4+ cell count increased sharply at the same time as lymph node histoplasmosis was diagnosed. This paradoxical response? the relapse of histoplasmosis and concomitant increase in CD4+ cell count and undetectable viral load after resumption of HAART ? suggests that this was a case of immune reconstitution inflammatory syndrome (IRIS).

Leprosy and HIV coinfection: a critical approach.

An increase in leprosy among HIV patients, similar to that observed in patients with TB, was expected approximately 20 years ago. Studies conducted in the 1990s together with those reported recently seemed to indicate that a coinfection with HIV did not alter the incidence and the clinical spectrum of leprosy and that each disease progressed as a single infection. By contrast, in countries with a high seroprevalence of HIV, TB was noted to increase. Explanations may be provided by the differences in the incubation time, the biology and toxicity of Mycobacterium leprae and Mycobacterium tuberculosis. After the introduction of HAART the leprosy-HIV coinfection manifested itself as an immune reconstitution inflammatory syndrome (IRIS), typically as paucibacillary leprosy with type 1 leprosy reaction. The incidence of leprosy in HIV-infected patients has never been properly investigated. IRIS-leprosy is probably underestimated and recent data showed that the incidence of leprosy in HIV patients under HAART was higher than previously thought.

Borreliose de Lyme / Lyme borreliosis

As borrelioses constituem um grupo de doenças infecciosas causadas por espiroquetas do gênero Borrelia. A borreliose de Lyme, também denominada doença de Lyme, é uma doença infecciosa, não contagiosa, causada por espiroquetas pertencentes ao complexo Borrelia burgdorferi Sensu Lato e transmitida, mais frequentemente, por picada de carrapatos do gênero Ixodes. A doença apresenta quadro clínico variado, podendo desencadear manifestações cutâneas, articulares, neurológicas e cardíacas.

Borreliosis is an infectious disease caused by spirochetes of the genus Borrelia. Lyme borreliosis, also known as Lyme disease, is a non-contagious infectious disease caused by spirochetes belonging to the complex Borrelia burgdorferi sensu lato and more often transmitted by the bite of infected ticks of the genus Ixodes.The disease is characterized by a varied clinical profile, which can trigger cutaneous, articular, neurological and cardiac manifestations.

Leprosy and HIV coinfection: a clinical, pathological, immunological, and therapeutic study of a cohort from a Brazilian referral center for infectious diseases.

BACKGROUND: Although awareness of the relevance of leprosy and human immunodeficiency virus (HIV) coinfection is increasing worldwide, several aspects of this co-occurrence are not fully understood. METHODS: We describe clinical, pathological, immunological, and therapeutic long-term follow-up of a cohort of 25 individuals with leprosy and HIV infection from Manaus, Amazonas. RESULTS: Careful description of our cohort indicates a higher prevalence of leprosy in an HIV-positive population than that in the general population. We also observed upgrading shifting of leprosy clinical forms after initiation of highly active antiretroviral therapy and multidrug therapy and an impact of HIV infection on leprosy granuloma formation, among other features. CONCLUSION: Taken together, these new insights allow the proposition of a classification system that includes (1) leprosy and HIV true coinfection, (2) opportunistic leprosy disease, and (3) leprosy related to highly active antiretroviral therapy.

Borrelia Burgdorferi "sensu lato" in Brazil: Occurrence confirmed by immunohistochemistry and focus floating microscopy.

In the present study, we report the occurrence of Lyme's borreliosis in patients from the Brazilian Amazon Region. Borreliosis was investigated by immunohistochemistry and focus floating microscopy for Borrelia burgdorferi in skin biopsy samples from 22 patients with both clinical and histopathology evidences compatible with Erythema Migrans. Spirochetes were detected by specific immunohistochemistry and focus floating microscopy for B. burgdorferi in samples from five patients. Clinical cure of the cutaneous lesions was observed in all the patients after treatment with doxycycline regimen as proposed by the Center Disease Control guidelines. A limitation of our study was the fact that we were not able to isolate and culture these organisms. These are the first known Brazilian cases of borreliosis to have Focus Floating Microscopy confirmation.

T regulatory cells and plasmocytoid dentritic cells in hansen disease: a new insight into pathogenesis?

Leprosy is characterized by spectrum of histologically different granulomatous skin lesions that reflects the patient's immune response to Mycobacterium leprae. Presence, frequency, and distribution of both CD4+ CD25+ FoxP3+ T regulatory cells (T-regs) and CD123+ plasmacytoid dendritic cells in leprosy have never been investigated. We performed a retrospective immunohistochemical study on 20 cases of leprosy [tuberculoid tuberculoid (TT): 1 patient; borderline tuberculoid (BT): 3 patients; borderline lepromatous (BL): 5 patients; lepromatous lepromatous (LL): 5 patients; borderline borderline in reversal reaction (BB-RR): 1 patient; BT-RR: 2 patients; and erythema nodosum leprosum (ENL): 3 patients]. FoxP3-positive cells were present in 95% of the cases with an average density of 2.9% of the infiltrate. Their distribution was not related to granulomatous structures or special locations. There was no statistical difference of FoxP3 expression between TT, BT, BL, and LL, whereas a statistical significant increment (P = 0.042) was observed in patients affected by reversal leprosy reactions (BT-RR and BB-RR) compared with patients affected by ENL and patients with nonreactional disease forms (BL, LL, BT, TT). CD123 expression was not observed in any of the biopsy specimens evaluated; with the exception of 2 cases of ENL, in which a focal positivity for CD123 was observed. Our results show that plasmacytoid dendritic cells are not involved in the immune response against M. leprae while T-regs are present in leprosy skin lesions. These data raise the question if T-regs have a pathogenetic role in HD as previously demonstrated in Leishmania major and Mycobacterium tuberculosis.

Tegumentary leishmaniasis as the cause of immune reconstitution inflammatory syndrome in a patient co-infected with human immunodeficiency virus and Leishmania guyanensis.

We report a case of immune reconstitution inflammatory syndrome (IRIS) in a 32-year-old man infected with human immunodeficiency virus and Leishmania guyanensis. Three months after initiation of highly active anti-retroviral therapy (HAART), the patient had disseminated cutaneous leishmaniasis and started anti-leishmanial therapy. The patient's leishmaniasis manifestations during HAART ranged form an anergic response (46 CD4+ T cells/microL) to a disseminated cutaneous leishmaniasis (112 CD4+ T cells/microL). Eight weeks later (168 CD4+ T cells/microL, skin biopsy specimens showed inflammatory infiltrates with no detectable amastigotes. The patient then became comatose. Prednisone therapy (60 mg/day) was initiated with a significant improvement within 48 hours. Three months later (CD4+ T cell count = 184 cell/microL), localized, classic, cutaneous leishmaniasis developed in the patient and anti-leishmanial treatment was re-introduced. On that occasion, frequency of T regulatory cells was 1.82% of all CD4+ cells. Our data suggest a pivotal role for CD4+ T cells in the onset of IRIS and lesion ulceration and their association with a low frequency of T regulatory cells.

Human immunodeficiency virus type- 1 subtypes of infected patients in Espírito Santo, Brazil

Genetic variability of human immunodeficiency virus type - 1(HIV-1) is a potential threat for both diagnosis and treatment of HIV/AIDS, as well as the development of effective vaccines. Up to now, HIV subtypes circulating among HIV-positive patients in the state of Espírito Santo were not known. In the present study, blood samples from 100 therapy-naïve HIV-1 infected patients were collected and the HIV subtype was determined through the Heteroduplex Mobility Assay (HMA). Ninety-seven out of 100 studied samples were subtyped by HMA, 73 samples (75.2 percent) were from subtype B, 9 (9.3 percent) from subtype F, 3 (3.1 percent) from subtype C, 6 (6.2 percent) Benv/Fgag, and another 6 (6.2 percent) Fenv/Bgag, what suggests that recombinant viruses were present in the studied samples. Twenty-eight percent of the subtype B samples were represented by the Brazilian B" subtype, which were identified by RFLP with Fok I. Data presented here demonstrate that the epidemiological characteristics of the HIV epidemic in the state of Espírito Santo are similar to those from the other Southeastern states and helped to better understand the genetic polymorphism of HIV in Brazil.

Nitric oxide levels are not changed in saliva of patients infected with hepatitis C virus

O objetivo desta investigacão foi avaliar os níveis de metabólitos do óxido nítrico na saliva de pacientes anti-vírus da hepatite C positivos na tentativa de correlacionar os níveis desses metabólitos com a presenca do VHC na saliva. Foram estudados 39 pacientes anti-VHC positivos (9 com enzimas hepáticas normais, 16 com hepatite crônica e 14 com cirrose hepática) e em 13 controles saudáveis, sem sinais ou sintomas de doenca hepática.O RNA do VHC foi identificado no soro e na saliva através de técnica de RT-PCR e os níveis de óxido nítrico foram avaliados pela quantificacão dos seus metabólitos estáveis, nitratos e nitritos. Os resultados demonstraram que os níveis de nitrito na saliva não diferiram significativamente no grupo anti-VHC positivo em relacão ao grupo controle, nem entre os grupo com presenca ou ausência do RNA do VHC na saliva. Os níveis de nitrito foram mais elevados no grupo com cirrose hepática do que nos grupos controle e anti-VHC positivos, sem cirrose hepática, mas as diferencas não foram estatisticamente significativas. A não observacão de níveis elevados de nitrito na saliva dos pacientes anti-VHC positivos é uma indicacão indireta de que a sialoadenite não deve ser freqüente nesses pacientes ou, se existe, é de intensidade não suficiente para modificar os níves de óxido nítrico na secrecão salivar.

Detection of hepatitis C virus RNA in saliva samples from patients with seric anti-HCV antibodies

We examined the frequency of HCV-RNA in saliva samples from anti-HCV positive patients. Both plasma and saliva samples from 39 HCV patients (13 with normal liver enzymes, 19 with abnormal liver enzymes and 13 with cirrhosis) were investigated. Stimulated saliva and fresh plasma were centrifuged (900 x g,10 min) and stored at -70°C, after the addition of guanidine isothiocyanate RNA extraction buffer. HCV-RNA was detected by RT- nested-PCR (amplification of HCV-cDNA for two rounds, using HCV primers 939/209 and 940/211). HCV genotyping was carried out by RFLP (using Mva I and Hinf 1 or Hae III and Rsa I restriction enzymes). Thirty-two out of 39 (82 percent; 95 percent CI=70-94 percent) anti-HCV-positive patients had HCV-RNA in plasma samples. Eight out of 39 (20.5 percent; 95 percent CI=6.6-34.4 percent) had HCV-RNA in the saliva. The HCV genotype in saliva samples from these patients matched the genotype found for plasma HCV-RNA. No significant correlation between the presence of HCV and either age, gender, HCV genotype or any risk factor for HCV infection was found. The observed prevalence (20.5 percent of anti HCV positive patients or 25 percent of the patients with HCV-RNA in plasma) was lower than that previously reported from other countries. The low frequency of HCV-RNA in saliva samples observed in our study may be due to the use of cell-free saliva. Other authors reporting higher frequencies of HCV-RNA in saliva used whole saliva, without centrifugation.

Longitudinal comparison between plasma and seminal HIV-1 viral loads during antiretroviral treatment

This study was designed to investigate the impact of anti-retroviral therapy on both plasma and seminal HIV-1 viral loads and the correlation between viral loads in these compartments after treatment. Viral load, CD4+ and CD8+ T-cell counts were evaluated in paired plasma and semen samples from 36 antiretroviral therapy-naïve patients at baseline and on days 45, 90, and 180 of treatment. Slopes for blood and seminal viral loads in all treated patients were similar (p = 0.21). Median HIV-1 RNA titers in plasma and semen at baseline were 4.95 log10 and 4.48 log10 copies/ml, respectively. After 180 days of therapy, the median viral load declined to 3.15 log10 copies/ml (plasma) and 3.2 log10 copies/ml (semen). At this timepoint 22 patients presented HIV-1 viral load below 400 copies/ml in either plasma or semen, but only 9 had viral loads below 400 copies/ml in both compartments.

Detection of Trypanosoma cruzi DNA within murine cardiac tissue sections by in situ polymerase chain reaction

The use of in situ techniques to detect DNA and RNA sequences has proven to be an invaluable technique with paraffin-embedded tissue. Advances in non-radioactive detection systems have further made these procedures shorter and safer. We report the detection of Trypanosoma cruzi, the causative agent of Chagas disease, via indirect and direct in situ polymerace chain reaction within paraffin-embedded murine cardiac tissue sections. The presence of three T. cruzi specific DNA sequences were evaluated: a 122 base pair (bp) sequence localized within the minicircle network, a 188 bp satellite nuclear repetitive sequence and a 177 bp sequence that codes for a flagellar protein. In situ hybridization alone was sensitive enough to detect all three T. cruzi specific DNA sequences

Intestinal nematodes and pulmonary tuberculosis

We report a significantly higher prevalence of intestinal nematodes in patients with pulmonary tuberculosis (TB) compared to a matched control group: 33/57 (57.8 percent) in patients with TB and 18/86 (20.9 percent) in the control group; OR=5.19; 95 percent CI= 2.33-11.69; p=0.000). When TB patients eosinophilia was also significantly higher among those with intestinal parasites (69.8 percent) compared to those without this condition (45.6 percent). We hypothesized that the immune modulation induced by nematodes is a factor that enhances TB infection/progression and that eosinophilia seen in TB patients is a consequence of helminth infection