Retrospective Cohort Study of COVID-19 in Patients of the Brazilian Public Health System with SARS-CoV-2 Omicron Variant Infection.

Several vaccines against COVID-19 are now available, based on different techniques and made by different laboratories spread around the world. With the roll out of the vaccination process in an advanced stage in many countries, the reduced risk of hospitalization due to the Omicron variant relative to the Delta variant infection, despite the higher transmission risk of Omicron, may lead to a misinterpretation of the results, as infection by Omicron is associated with a significant reduction in severe outcomes and shorter hospitalization time than the Delta variant. We compared the in-hospital mortality due to the Omicron (Jan-Mar 2022) with Gamma (Jan 2021) and Delta (Oct-Dec 2021) variants of patients in the Brazilian public health system. This study also discusses the decrease in booster vaccine effectiveness in patients hospitalized due to the Omicron variant compared with the Delta variant. Without a remodeling of vaccines for new variants, booster doses may be necessary with a shorter time interval.

The successful use of radiofrequency-induced heat therapy for cutaneous leishmaniasis: a review.

The present gold standard of the treatment of cutaneous leishmaniasis (CL) is pentavalent antimonials either sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime), These drugs are quite toxic. They are given by injection and usually administered intramuscularly or intravenously for three weeks or intralesionally for seven or more weeks. That is why the successful introduction of radiofrequency-induced heat therapy using a Thermomed™ 1.8 instrument administered in a single application, with minimal toxic effects, is so important for the treatment of CL.

Four days a week or less on appropriate anti-HIV drug combinations provided long-term optimal maintenance in 94 patients: the ICCARRE project.

Short, intraweekly cycles of anti-HIV combinations have provided intermittent, effective therapy (on 48 patients) (1). The concept is now extended to 94 patients on treatment, 4 days per week or less, over a median of 2.7 discontinuous treatment years per patient. On suppressive combinations, 94 patients volunteered to treatment, 5 and 4 days per week, or reduced stepwise to 4, 3, 2, and 1 days per week in 94, 84, 66, and 12 patients, respectively, on various triple, standard, antiviral combinations, or nonregistered, quadruple, antiviral combinations. Ninety-four patients on treatment 4 days per week aggregated 165 intermittent treatment years; no viral breakthrough was observed over 87 average treatment weeks per patient, 63 of 94 having passed 2.5 intermittent treatment years on any of the antiviral combinations prescribed. On the hyperintermittent treatment of 3, 2, and 1 days per week, HIV RNA surged >50 copies, 4 weeks apart, in 18 instances (6.8 viral escapes/100 hyperdiscontinuous maintenance years). Viral escapes could have been a result of erratic adherence (EA) to regimen or follow-up (3 patients)--drug taken at half of the daily recommended dosage (8 patients) and/or overlooked archival-resistant HIVs from antecedent treatment failures (6 patients). Aside from the above circumstances, HIV unexpectedly rebounded in 3 patients on 2 days per week treatment and 1 patient on 1 day per week treatment, posting 2.2 intrinsic viral escapes/100 highly discontinuous treatment years. All 18 escapes were eventually reversed by 7 days per week salvage combinations, and 11 of 18 patients have been back for a second course of intermittent therapy, 4 days per week or less. Both cell-activation markers on the surface of T lymphocytes and cell-bound HIV DNA levels remained stable or declined. CD4/CD8 ratios rose to ≥1 in 35% of patients, whereas CD4 counts went ≥500/µl in 75%. These values were previously 7 and 40%, respectively, on 7 days per week therapy. In our aging, long, HIV-enduring, multitreated patient cohort, treatment 4 days per week and less over 421 intermittent treatment years reduced prescription medicines by 60%--equivalent to 3 drug-free/3 virus-free remission year per patient--actually sparing €3 million on just 94 patients at the cost of 2.2 intrinsic viral failure/100 hyperintermittent treatment years. At no risk of viral escape, maintenance therapy, 4 days per week, would quasiuniversally offer 40% cuts off of current overprescriptions.

Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis.

Macrophage migration inhibitory factor (MIF), an innate cytokine encoded in a functionally polymorphic genetic locus, contributes to detrimental inflammation but may be crucial for controlling infection. We explored the role of variant MIF alleles in tuberculosis. In a Ugandan cohort, genetic low expressers of MIF were 2.4-times more frequently identified among patients with Mycobacterium tuberculosis (TB) bacteremia than those without. We also found mycobacteria-stimulated transcription of MIF and serum MIF levels to be correlated with MIF genotype in human macrophages and in a separate cohort of US TB patients, respectively. To determine mechanisms for MIF's protective role, we studied both aerosolized and i.v. models of mycobacterial infection and observed MIF-deficient mice to succumb more quickly with higher organism burden, increased lung pathology, and decreased innate cytokine production (TNF-α, IL-12, IL-10). MIF-deficient animals showed increased pulmonary neutrophil accumulation but preserved adaptive immune response. MIF-deficient macrophages demonstrated decreased cytokine and reactive oxygen production and impaired mycobacterial killing. Transcriptional investigation of MIF-deficient macrophages revealed reduced expression of the pattern recognition receptor dectin-1; restoration of dectin-1 expression recovered innate cytokine production and mycobacterial killing. Our data place MIF in a crucial upstream position in the innate immune response to mycobacteria and suggest that commonly occurring low expression MIF alleles confer an increased risk of TB disease in some populations.

Cutting edge: Deficiency of macrophage migration inhibitory factor impairs murine airway allergic responses.

Increased levels of macrophage migration inhibitory factor (MIF) in serum, sputum, and bronchioalveolar lavage fluid (BALF) from asthmatic patients and time/dose-dependent expression of MIF in eosinophils in response to phorbol myristate acetate suggest the participation of MIF in airway inflammation. In this study, we examined inflammation in OVA-sensitized mouse lungs in wild-type and MIF-deficient mice (MIF(-/-)). We report increased MIF in the lung and BALF of sensitized wild-type mice. MIF(-/-) mice demonstrated significant reductions in serum IgE and alveolar inflammatory cell recruitment. Reduced Th1/Th2 cytokines and chemokines also were detected in serum or BALF from MIF(-/-) mice. Importantly, alveolar macrophages and mast cells, but not dendritic cells or splenocytes, from MIF(-/-) mice demonstrated impaired CD4+ T cell activation, and the reconstitution of wild-type mast cells in MIF(-/-) mice restored the phenotype of OVA-induced airway inflammation, revealing a novel and essential role of mast cell-derived MIF in experimentally induced airway allergic diseases.

Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of bone and cartilage, which is mediated, in part, by synovial fibroblasts. Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes responsible for matrix degradation. Macrophage migration inhibitory factor (MIF) is a cytokine that induces the production of a large number of proinflammatory molecules and has an important role in the pathogenesis of RA by promoting inflammation and angiogenesis. In the present study, we determined the role of MIF in RA synovial fibroblast MMP production and the underlying signaling mechanisms. We found that MIF induces RA synovial fibroblast MMP-2 expression in a time-dependent and concentration-dependent manner. To elucidate the role of MIF in MMP-2 production, we produced zymosan-induced arthritis (ZIA) in MIF gene-deficient and wild-type mice. We found that MMP-2 protein levels were significantly decreased in MIF gene-deficient compared with wild-type mice joint homogenates. The expression of MMP-2 in ZIA was evaluated by immunohistochemistry (IHC). IHC revealed that MMP-2 is highly expressed in wild-type compared with MIF gene-deficient mice ZIA joints. Interestingly, synovial lining cells, endothelial cells, and sublining nonlymphoid mononuclear cells expressed MMP-2 in the ZIA synovium. Consistent with these results, in methylated BSA (mBSA) antigen-induced arthritis (AIA), a model of RA, enhanced MMP-2 expression was also observed in wild-type compared with MIF gene-deficient mice joints. To elucidate the signaling mechanisms in MIF-induced MMP-2 upregulation, RA synovial fibroblasts were stimulated with MIF in the presence of signaling inhibitors. We found that MIF-induced RA synovial fibroblast MMP-2 upregulation required the protein kinase C (PKC), c-jun N-terminal kinase (JNK), and Src signaling pathways. We studied the expression of MMP-2 in the presence of PKC isoform-specific inhibitors and found that the PKCdelta inhibitor rottlerin inhibits MIF-induced RA synovial fibroblast MMP-2 production. Consistent with these results, MIF induced phosphorylation of JNK, PKCdelta, and c-jun. These results indicate a potential novel role for MIF in tissue destruction in RA.

Heat therapy for cutaneous leishmaniasis elicits a systemic cytokine response similar to that of antimonial (Glucantime) therapy.

Controlled heat delivered as radio waves has been used successfully in the treatment of cutaneous leishmaniasis (CL). Here we investigated whether local heat therapy has systemic effects, as measured by the modulation of cytokine production following heat therapy of CL lesions compared with antimonial (Glucantime) treatment. Patients with CL were randomly assigned into this study. Heat (50 degrees C for 30s) was applied once. The control group received Glucantime therapy for 20 d. Cytokine production by peripheral blood mononuclear cells was assayed on days 0, 14 and 28 after onset of treatment. At the end of 28 d, 75% of lesions were healing or healed in the heat therapy group and 90% in the control group (P=0.1261). There was a decrease in IFN-gamma, IL-5 and TNF-alpha levels comparing day 0 with day 28 in both groups, but no difference between the two therapy groups. In patients with only one of several lesions treated with heat therapy, the untreated lesions also healed. Local heat therapy in CL lesions leads to systemic cytokine responses similar to that induced by systemic Glucantime therapy.

Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia.

Calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide present in central and peripheral neurons, is released at inflammatory sites and inhibits several macrophage, dendritic cell, and lymphocyte functions. In the present study, we investigated the role of CGRP in models of local and systemic acute inflammation and on macrophage activation induced by lipopolysaccharide (LPS). Intraperitoneal pretreatment with synthetic CGRP reduces in approximately 50% the number of neutrophils in the blood and into the peritoneal cavity 4 h after LPS injection. CGRP failed to inhibit neutrophil recruitment induced by the direct chemoattractant platelet-activating factor, whereas it significantly inhibited LPS-induced KC generation, suggesting that the effect of CGRP on neutrophil recruitment is indirect, acting on chemokine production by resident cells. Pretreatment of mice with 1 mug of CGRP protects against a lethal dose of LPS. The CGRP-induced protection is receptor mediated because it is completely reverted by the CGRP receptor antagonist, CGRP 8-37. The protective effect of CGRP correlates with an inhibition of TNF-alpha and an induction of IL-6 and IL-10 in mice sera 90 min after LPS challenge. Finally, CGRP significantly inhibits LPS-induced TNF-alpha released from mouse peritoneal macrophages. These results suggest that activation of the CGRP receptor on macrophages during acute inflammation could be part of the negative feedback mechanism controlling the extension of acute inflammatory responses.

Macrophage accumulation and renal fibrosis are independent of macrophage migration inhibitory factor in mouse obstructive nephropathy.

BACKGROUND AND AIM: The progression of renal injury, initiated by either an immune or non-immune insult, is closely associated with the accumulation of leucocytes and fibroblasts in the damaged kidney. Macrophage migration inhibitory factor (MIF) regulates leucocyte activation and fibroblast proliferation in vitro. Studies have identified a pathological role for MIF in immune-initiated renal injury in the rat. In this study, we examined the role of MIF in obstructive nephropathy, where renal injury is initiated by a non-immune insult. METHODS AND RESULTS: Unilateral ureteric ligation was performed on MIF wildtype (+/+) and MIF deficient (-/-) mice. Groups of five mice were killed at days 0, 1, 5 or 10 after obstruction, and kidneys were examined via immunohistochemistry and northern blotting. In MIF +/+ mice, expression of the MIF protein increased in obstructed kidneys compared to normal control kidneys. Interstitial macrophage and T cell accumulation was significantly increased in obstructed kidneys at day 5 and 10, but was unaffected by MIF deficiency. Osteopontin and macrophage colony stimulating factor (M-CSF) mRNA expression in obstructed kidneys were equally increased in both genotypes, indicating that expression of these chemokines is not influenced by MIF. No difference was detected in the development of renal fibrosis in obstructed MIF +/+ and MIF -/- kidneys, as assessed by myofibroblast accumulation and proliferation and expression of profibrotic molecules (transforming growth factor-beta 1(TGF-beta1) and collagen). CONCLUSION: These results demonstrate that MIF expression is increased in obstructive nephropathy without affecting kidney leucocyte accumulation or the development of renal fibrosis. This suggests that the progression of renal injury in obstructive nephropathy is independent of MIF.

Reduced leukocyte-endothelial cell interactions in the inflamed microcirculation of macrophage migration inhibitory factor-deficient mice.

OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with established roles in a range of inflammatory conditions. However, it is not known whether MIF influences inflammation via the direct promotion of leukocyte-endothelial cell interactions. Therefore, the aim of these experiments was to investigate the ability of MIF to regulate leukocyte-endothelial cell interactions in the inflamed microvasculature. METHODS: Intravital microscopy was used to examine postcapillary venules in the cremaster muscle and synovium of wild-type and MIF(-/-) mice. Leukocyte-endothelial cell interactions (rolling, adhesion, emigration) were compared under a range of inflammatory conditions. RESULTS: In cremasteric postcapillary venules of MIF(-/-) mice, lipopolysaccharide (LPS)-induced leukocyte rolling, adhesion, and emigration were significantly reduced relative to that in wild-type mice. Similar responses were observed in response to tumor necrosis factor alpha and histamine. Examination of the synovial microvasculature following exposure to carrageenan revealed that leukocyte rolling and adhesion in synovial postcapillary venules and leukocyte entry into the joint space were also reduced significantly in MIF(-/-) mice. In each of these models, the level of P-selectin-dependent rolling was reduced in MIF(-/-) mice. Despite this, no difference in P-selectin expression was observed following LPS treatment. However, microvascular shear forces were elevated in MIF(-/-) mice, raising a possible mechanism to explain the reduced interactions in these animals. CONCLUSION: MIF(-/-) mice consistently displayed a reduction in P-selectin-dependent rolling, suggesting that MIF exerts proinflammatory effects, in part, via the promotion of P-selectin-mediated rolling. Together, these data indicate that MIF promotes interactions between leukocytes and endothelial cells, thereby enhancing the entry of leukocytes into sites of inflammation.

Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine expressed widely by vascular cells. However, scant in vivo evidence supports direct participation of MIF in atherogenesis. Therefore, we investigated whether deficiency of MIF modulates atherosclerotic lesion formation and composition in low-density lipoprotein receptor-deficient (LDLr-/-) mice. METHODS AND RESULTS: MIF-/-LDLr-/- and LDLr-/- mice were generated and consumed an atherogenic diet for 12 or 26 weeks. MIF-/-LDLr-/- mice had significantly reduced abdominal aorta lipid deposition and intimal thickening from aortic arch throughout the abdominal aorta compared with LDLr-/- mice. Marked retardation of atherosclerosis over time in MIF-deficient mice accompanied decreased lesion cell proliferation. At 26 weeks, 20% of MIF-deficient mice developed only early, fatty streak-like lesions, whereas >80% of LDLr-/- mice developed advanced lesions containing calcification and lipid cores. Analysis of smooth muscle cells from mouse aortae demonstrated that MIF deficiency reduced smooth muscle cell proliferation, cysteine protease expression, and elastinolytic and collagenolytic activities. CONCLUSIONS: Deficiency of MIF reduces atherogenesis in LDLr-/- mice. These results provide novel insight into inflammatory pathways operating in atheromata and identify a new potential target for modulating atherogenesis.

Blockade of macrophage migration inhibitory factor does not prevent acute renal allograft rejection.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory molecule involved in cell-mediated immunity and delayed-type hypersensitivity (DTH). We inhibited systemic and local MIF production to determine its contribution to acute rejection (AR). Skin DTH response and acute rejection of skin and kidney allografts were examined using MIF gene knockout (MIF -/-) and wild-type mice (MIF +/+) with anti-MIF or control antibody. MIF-Ab reduced skin DTH by 60% (p < 0.01), but absence of the MIF gene (MIF -/-) had no effect. Local absence of MIF had no effect on the survival of skin grafted onto BALB/c recipients. Similarly MIF +/+ and MIF -/- kidneys transplanted into BALB/c recipients showed a similar degree of histological rejection, graft dysfunction and cellular infiltrate suggesting that AR is not dependent on local MIF production. To investigate the influence of systemic MIF, BALB/c donor skin was grafted onto MIF +/+ and MIF -/- mice. The tempo of AR was not altered by systemic absence of MIF (MIF-Ab or MIF -/-). BALB/c kidneys transplanted into MIF +/+ (with or without MIF-Ab) and MIF -/- mice showed similar parameters of rejection. MIF blockade reduces the DTH response; however, neither local nor systemic MIF are required for the rejection of fully mismatched skin and renal allografts.

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis.

OBJECTIVE: To study the capacity of macrophage migration inhibitory factor (MIF) to regulate proliferation, apoptosis, and p53 in an animal model of rheumatoid arthritis (RA) and in fibroblast-like synoviocytes (FLS) from humans with RA. METHODS: Antigen-induced arthritis (AIA) was induced in MIF(-/-) mice and littermate controls. FLS were obtained from patients with RA. Western blotting and immunohistochemistry were used to measure p53 in cells and tissues. Apoptosis was detected in cells by flow cytometry using TUNEL and annexin V/propidium iodide labeling. Apoptosis in tissue was detected using TUNEL. Proliferation was assessed in cultured cells and tissue by (3)H-thymidine incorporation and Ki-67 immunostaining, respectively. RESULTS: MIF inhibited p53 expression in human RA FLS. Levels of p53 were correspondingly increased in MIF(-/-) mouse tissues and cells. Spontaneous and sodium nitroprusside-induced apoptosis were significantly increased in MIF(-/-) cells. In vitro exposure of FLS to MIF reduced apoptosis and significantly induced FLS proliferation. Synoviocyte proliferation in MIF(-/-) mice was correspondingly reduced. A decrease in the severity of AIA in MIF(-/-) mice was associated with an increase in p53 and apoptosis in synovium. Evidence of in situ proliferation was scant in this model, and no difference in in situ proliferation was detectable in MIF(-/-) mice compared with wild-type mice. CONCLUSION: These results indicate a role for MIF in the regulation of p53 expression and p53-mediated events in the inflamed synovium and support the hypothesis that MIF is of critical importance in the pathogenesis of RA.

Altered T helper responses in CD40 and interleukin-12 deficient mice reveal a critical role for Th1 responses in eliminating the helminth parasite Taenia crassiceps.

A key feature of helminth infections is the induction of strong Th2-biased immune responses in their hosts. We have previously found that Th2-like responses mediate susceptibility to the helminth parasite Taenia crassiceps, probably by inhibiting Th1 responses required for the development of protective immunity against this parasite. Here we show that mice lacking interleukin-12p35 (IL-12p35-/-) following T. crassiceps infection, failed to mount a Th1 response, but developed a strong Th2-type response, produced higher levels of IgG1, IgE, interleukin-4, interleukin-5 as well as interleukin-13 than wild-type mice, and became highly susceptible to the larval stage of this cestode. In contrast, similarly-infected CD40 deficient BALB/c mice (CD40-/-) displayed impairment of both Th1 and Th2-type responses associated with low levels of interferon-gamma as well as IgE, interleukin-4, interleukin-5 and interleukin-13, but efficiently controlled T. crassiceps infection. Together, these findings suggest a detrimental role for Th2-biased responses during the larval stage of T. crassiceps infection. Furthermore, they also suggest a pivotal role for CD40 in developing Th2-type responses.

Macrophage migration inhibitory factor plays a critical role in mediating protection against the helminth parasite Taenia crassiceps.

To determine the role of endogenous migration inhibitory factor (MIF) in regulation of immune response during murine cysticercosis caused by the helminth parasite Taenia crassiceps, we analyzed the course of T. crassiceps infection in MIF(-/-) BALB/c mice. MIF(-/-) mice were highly susceptible to T. crassiceps and developed significantly higher parasite loads compared to similarly infected MIF(+/+) mice. Throughout the course of infection, Taenia crassiceps soluble antigen-stimulated spleen cells from both MIF(+/+) and MIF(-/-) mice produced significant and comparable levels of interleukin-4 (IL-4), but those from MIF(-/-) mice produced significantly more IL-13, as well as gamma interferon (IFN-gamma), suggesting that the susceptibility of MIF(-/-) mice to T. crassiceps was not due to the lack of IFN-gamma production. Interestingly, low levels of both total and specific immunoglobulin G2a were observed in MIF(-/-) cysticercotic mice despite the high IFN-gamma levels; in addition, peritoneal macrophages obtained from T. crassiceps-infected MIF(-/-) mice at different time points failed to respond efficiently to stimulation in vitro with lipopolysaccharide plus IFN-gamma and produced significantly lower levels of IL-12, tumor necrosis factor alpha, and NO compared to those from MIF(+/+) mice. These findings demonstrate that MIF plays a critical role in mediating protection against T. crassiceps in vivo. Moreover, these findings also suggest that impaired macrophage function rather than the lack of Th1 development may be responsible for mediating susceptibility to T. crassiceps.

Macrophage migration inhibitory factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium.

The cytokine macrophage migration inhibitory factor (MIF) exerts a multitude of biological functions. Notably, it induces inflammation at the interface between the immune system and the hypothalamus-pituitary-adrenal stress axis. The role of MIF in infectious diseases is not understood completely. Here, we show that MIF-deficient (MIF(-/-)) knockout mice fail to control an infection with wild-type Salmonella typhimurium. Increased susceptibility was accompanied by a reduced Th1 response, demonstrated by decreased levels of IL-12, IFNgamma, and tumor necrosis factor alpha. In Salmonella-infected MIF(-/-) mice, levels of IL-1beta were markedly increased. Additionally, infected MIF(-/-) mice showed elevated serum levels of nitric oxide and corticosterone as compared with control mice. Our results point to MIF as a key mediator in the host response to S. typhimurium. MIF not only promotes development of a protective Th1 response but ameliorates disease by altering levels of reactive nitrogen intermediates and corticosteroid hormones, which both exert immunosuppressive functions.

Asymptomatic human carriers of Leishmania chagasi.

In Brazil, programs based on elimination of infected dogs have not curtailed the spread of visceral leishmaniasis (VL), suggesting that other reservoirs of infection exist. Persons with active VL can infect the sand fly vector, but in endemic areas, persons with asymptomatic infections, whose infectivity to sand flies is unknown, are far more numerous. In this study, a polymerase chain reaction-based assay detected kinetoplast DNA of Leishmania chagasi in the blood of eight of 108 asymptomatic persons living with patients with recently diagnosed VL. These eight persons had low or unmeasurable levels of IgG antibodies to Leishmania, demonstrating the insensitivity of serology for subclinical infection. All eight persons had positive leishmanin skin test results, as did 70% of persons living in households of persons with active VL. Even if a small proportion of such asymptomatic persons are infective to sand flies, they represent a formidable reservoir of infection in endemic areas.

The urban spread of visceral leishmaniasis: clues from spatial analysis.

BACKGROUND: The pattern of spread of visceral leishmaniasis in Brazilian cities is poorly understood. METHODS: We used geographic information systems and spatial statistics to evaluate the distribution of 1061 cases of visceral leishmaniasis in Teresina, Brazil, in 1993 through 1996. RESULTS: A locally weighted (LOESS) regression model, which was fit as a smoothed function of spatial coordinates, demonstrated large-scale variation, with high incidence rates in peripheral neighborhoods that bordered forest land and pastures. Moran's I indicated small-scale variation and clustering up to 300 m, roughly the flight range of the sand fly vector. CONCLUSIONS: Spatial analytical techniques can identify high-risk areas for targeting control interventions.

Cutting edge: susceptibility to the larval stage of the helminth parasite Taenia crassiceps is mediated by Th2 response induced via STAT6 signaling.

Using STAT6(-/-) BALB/c mice, we analyzed the role of STAT6-induced Th2 response in determining the outcome of murine cysticercosis caused by the helminth parasite Taenia crassiceps. After T. crassiceps infection, wild-type BALB/c mice developed a strong Th2-like response; produced high levels of IgG1, IgE, IL-4, as well as IL-13; and remained susceptible to T. crassiceps. In contrast, similarly infected STAT6(-/-) mice mounted a strong Th1-like response; produced high levels of IgG2a, IL-12, IFN-gamma, as well as nitric oxide; and efficiently controlled T. crassiceps infection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to T. crassiceps and, furthermore, that unlike the case in most helminths, immunity against T. crassiceps is mediated by a Th1-like rather than Th2-like response.

Deltamethrin-impregnated dog collars have a potent anti-feeding and insecticidal effect on Lutzomyia longipalpis and Lutzomyia migonei

Deltamethrin-impregnated PVC dog collars were tested to assess if they were effective in protecting dogs from sand fly bites of Lutzomyia longipalpis and Lu. migonei. A protective effect against Old World species Phlebotomus perniciosus was demonstrated before. Four dogs wearing deltamethrin collars and three dogs wearing untreated collars (not impregnated with deltamethrin) were kept in separate kennels for over eight months in a village on the outskirts of Fortaleza in Cearß, Brazil. Periodically, a dog from each group was sedated, placed in a net cage for 2 h in which 150 female sand flies had been released 10-15 min before. Lu. longipalpis were used 4, 8, 12, 16, 22, 27, and 35 weeks after the attachment of the collars. Lu. migonei were used 3, 7, 11, 15, 22, 26, and 36 weeks after attachment. During 35 weeks, only 4.1 percent (81 of 2,022) Lu. longipalpis recovered from the nets with the deltamethrin collared dogs were engorged, an anti-feeding effect of 96 percent. Mortality initially was over 90 percent and at 35 weeks was 35 percent with half of the sand flies dying in the first 2 h. In contrast, 83 percent of the 2,094 Lu. longipalpis recovered from the nets containing the untreated collared dogs were engorged and the mortality ranged from zero to 18.8 percent on one occasion with 1.1 percent dying in the first 2 h. Similar findings were found with Lu. migonei: of 2,034 sand flies recovered over this period, only 70 were engorged, an anti-feeding effect of 96.5 percent, and mortality ranged from 91 percent initially to 46 percent at 36 weeks. In contrast, engorgement of controls ranged from 91 to71 percent and a mortality ranged from 3.5 to 29.8 percent. These studies show that deltamethrin impregnated collars can protect dogs against Brazilian sand flies for up to eight months. Thus, they should be useful in a program to control human and canine visceral leishmaniasis