Martin Montes

Strongyloides stercoralis: There but not seen

Purpose of review Diagnosis of Strongyloides stercoralis is often delayed owing to patients presenting with nonspecific gastrointestinal complaints, a low parasite load and irregular larval output. Although several diagnostic methods exist to detect the presence of S. stercoralis there is no gold standard. In immunocompromised hosts (patients with malignancy, organ transplantation or concurrent human T-cell-lymphocytic virus 1 infection or those on corticosteroid therapy), autoinfection can go unchecked with large numbers of invasive Strongyloides larvae disseminating widely and causing hyperinfection with dissemination, which can be fatal. This review will highlight current published research on improved diagnostic methods for S. stercoralis and the immune mechanisms thought to be responsible for hyperinfection syndrome. Recent findings Recent advances in diagnosis of S. stercoralis include a luciferase immunoprecipitation system that shows increased sensitivity and specificity to detect S. stercoralis-specific antibodies and a real-time quantitative PCR method to detect S. stercoralis in fecal samples. The severe clinical manifestations of S. stercoralis observed in human T-cell-lymphocytic virus 1 coinfected patients has been associated with an increased proportion of regulatory T cells that may be responsible for blunting otherwise effective granulocyte responses. Summary Strongyloidiasis is a major global health challenge that is underestimated in many countries. Novel diagnostic methods are expected to improve epidemiological studies and control efforts for prevention and treatment of strongyloidiasis. More studies are needed to unveil the mechanisms of severe clinical manifestations of human strongyloidiasis.

Regulatory T Cell Expansion in HTLV-1 and Strongyloidiasis Co-infection Is Associated with Reduced IL-5 Responses to Strongyloides stercoralis Antigen

Background Human strongyloidiasis varies from a chronic but limited infection in normal hosts to hyperinfection in patients treated with corticosteroids or with HTLV-1 co-infection. Regulatory T cells dampen immune responses to infections. How human strongyloidiasis is controlled and how HTLV-1 infection affects this control are not clear. We hypothesize that HTLV-1 leads to dissemination of Strongyloides stercoralis infection by augmenting regulatory T cell numbers, which in turn down regulate the immune response to the parasite. Objective To measure peripheral blood T regulatory cells and Strongyloides stercoralis larval antigen-specific cytokine responses in strongyloidiasis patients with or without HTLV-1 co-infection. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from newly diagnosed strongyloidiasis patients with or without HTLV-1 co-infection. Regulatory T cells were characterized by flow cytometry using intracellular staining for CD4, CD25 and FoxP3. PBMCs were also cultured with and without Strongyloides larval antigens. Supernatants were analyzed for IL-5 production. Results Patients with HTLV-1 and Strongyloides co-infection had higher parasite burdens. Eosinophil counts were decreased in the HTLV-1 and Strongyloides co-infected subjects compared to strongyloidiasis-only patients (70.0 vs. 502.5 cells/mm3, p = 0.09, Mann-Whitney test). The proportion of regulatory T cells was increased in HTLV-1 positive subjects co-infected with strongyloidiasis compared to patients with only strongyloidiasis or asymptomatic HTLV-1 carriers (median = 17.9% vs. 4.3% vs. 5.9 p<0.05, One-way ANOVA). Strongyloides antigen-specific IL-5 responses were reduced in strongyloidiasis/HTLV-1 co-infected patients (5.0 vs. 187.5 pg/ml, p = 0.03, Mann-Whitney test). Reduced IL-5 responses and eosinophil counts were inversely correlated to the number of CD4+CD25+FoxP3+ cells. Conclusions Regulatory T cell counts are increased in patients with HTLV-1 and Strongyloides stercoralis co-infection and correlate with both low circulating eosinophil counts and reduced antigen-driven IL-5 production. These findings suggest a role for regulatory T cells in susceptibility to Strongyloides hyperinfection.

Foxp3+ regulatory T cells in antiretroviral-naive HIV patients

We characterized regulatory T cells from antiretroviral-naive HIV patients by flow cytometry. The proportion of CD4 cells positive for CD25 and Foxp3 was increased, mainly in those with CD4 cell counts less than 200 cells/μl. The total number of Foxp3-positive cells correlated with the CD4 cell count. Further studies are needed on whether Foxp3-positive cell numbers or function explain the susceptibility to autoimmune and inflammatory diseases seen in some patients with advanced HIV.

Cryopreservation modulates the detection of regulatory T cell markers

Regulatory T cells (Tregs) modulate the host response in infectious diseases and are key mediators of peripheral tolerance. Cryopreservation of peripheral blood mononuclear cells (PBMCs) is commonly used in immunological field studies where access to complex laboratory tests is not feasible. Our objective is to assess the effects of cryopreservation on the flow cytometric detection of surface and intracellular markers of Tregs.

Normalization of FoxP3+ Regulatory T Cells in Response to Effective Antiretroviral Therapy

Regulatory T cells (Tregs) blunt uncontrolled immune responses. In advanced human immunodeficiency virus (HIV) infection, the total number of Tregs is decreased, but the proportion of T cells with a regulatory phenotype is highly variable. We studied CD4(+)CD25(+)FoxP3(+) T cells from patients successfully treated with combination antiretroviral therapy (ART). The proportion of CD4(+)CD25(+)FoxP3(+) cells transiently increased and then decreased from a median of 13% at baseline to 5.1% at 48 weeks, similar to values in normal subjects. These data suggest that with effective therapy, the regulatory cell numbers normalize, and that the inflammatory signals driving their production may also abate.

Strongyloides stercoralis infection complicating the central nervous system.

Strongyloides stercoralis is a nematode endemic in humid tropical regions. The life cycle of this parasite is complex and unique due to its capacity to cause autoinfection, resulting in chronic infections. Innate and adaptive immune responses are responsible for clearing the parasite. Many risk factors have been described, but the most important is living in or having visited an endemic area. The clinical presentation of strongyloidiasis is varied and ranges from asymptomatic chronic infection to hyperinfection syndrome. Hyperinfection syndrome is more common in patients with immunosuppresion due to therapy with corticosteroids, coinfection with human T-lymphotropic virus type I (HTLV-1), transplant patients, or patients receiving chemotherapy. Multiplication and migration of large parasite numbers cause worsening of the initial symptoms and leads to a high mortality rate. CNS involvement in strongyloidiasis has only been seen in patients with hyperinfection syndrome. Meningitis is the most common form of CNS involvement and gram-negative bacteria are the more frequent etiology. Repeated stool samples with concentration methods have a good sensitivity and specificity. In patients that are not from endemic areas serum antibody tests may be useful in the diagnosis. Treatment with a single dose of ivermectin is recommended for most patients. In severe or hyperinfection cases repeated doses may be needed.

Altered Eosinophil Proteome in a Patient with Hypereosinophilia from Acute Fascioliasis

ABSTRACT We used comparative proteomics to analyze eosinophils from a patient with hypereosinophilia due to fascioliasis. Using 2-dimensional electrophoresis and mass spectrometry, we demonstrated that the eosinophil proteome was significantly altered compared to those of healthy controls.

Infection and Hyperinfection with Strongyloides stercoralis: Clinical Presentation, Etiology of Disease, and Treatment Options

Human strongyloidiasis is a neglected global parasitic disease that affects large populations, especially in poorer regions of the world. Improved diagnostic tools, including serology and molecular tests, are demonstrating that the prevalence of infection is far higher than previously thought. Most complications arise as a consequence of delayed diagnosis, primarily due to physicians not considering this potentially lethal parasitic infection. The likelihood of developing mild chronic strongyloidiasis or hyperinfection syndrome depends on the status of the host defenses. The critical host responses controlling Strongyloides stercoralis in animal models include eosinophils, neutrophils, and antibodies. Corticosteroid treatment and human T-lymphotropic virus (HTLV)-1 infection predispose to hyperinfection in humans, but how these result in hyperinfection is poorly defined. Improved diagnostic tests and molecular epidemiology are highlighting the underappreciated burden of disease, which could be addressed with mass chemotherapy with proven effective drugs like ivermectin.

CD4+ T cell subsets and tax expression in HTLV-1 associated diseases

Abstract Human T lymphotropic virus type 1 (HTLV-1) infection displays variable clinical manifestations. These include inflammatory diseases such as HTLV-1 associated myelopathy (HAM) or immunosuppressive conditions such as Strongyloides stercoralis hyperinfection. The viral protein, Tax causes activation and proliferation of T cells. We hypothesize that the expression of Tax in T cell subsets characterizes the clinical manifestations of HTLV-1. To test this hypothesis, we measured T helper 1 effector cells and regulatory T cells (Tregs) among Tax expressing lymphocytes from peripheral blood mononuclear cells (PBMCs) of 32 HTLV-1 infected patients with HAM, with S. stercoralis co-infection or with asymptomatic infection. We observed increased ratios of Th1/Treg among Tax expressing lymphocytes in HAM patients. These data suggest that the expression of Tax among the different target cells may explain the variable presentation of HTLV-1.

Regulatory t-cell dynamics in cutaneous and mucocutaneous leishmaniasis due to leishmania braziliensis

To evaluate the dynamics of regulatory T cells (Tregs) during tegumentary leishmaniasis, we assessed peripheral blood and biopsies from 54 patients. Patients with cutaneous leishmaniasis (CL) had a decreased proportion of Tregs in the peripheral blood, but the proportion was higher in the biopsies of lesions. During treatment of CL, circulating Tregs increased reaching normal proportions, whereas antigen-specific interferon-γ responses diminished. By contrast, circulating Tregs from mucosal leishmaniasis patients failed to normalize during treatment. C-C chemokine receptor type 5 was expressed on a large proportion of Tregs at the site of infection. These results demonstrate increased Tregs at the site of infection, possibly homing from the peripheral circulation.