Melissa A. Law

Filaria-Induced Immune Evasion: Suppression by the Infective Stage of Brugia malayi at the Earliest Host-Parasite Interface

To assess the physiologic interactions between the infective stage of Brugia malayi—one of the extracellular parasites responsible for lymphatic filariasis in humans—and the APC with which they come in contact during their development and routes of travel, we have investigated the interaction between the infective stage (L3) of B. malayi and human Langerhans cells (LC) in the skin. Our data indicate that live L3 result in increased migration of LC from the epidermis without affecting the viability of these cells and up-regulation of the IL-18 cytokine involved in LC migration. Live L3 also result in down-regulation of MHC class I and II on the LC cell surface. Additionally, microarray data indicate that live L3 significantly down-regulated expression of IL-8 as well as of multiple genes involved in Ag presentation, reducing the capacity of LC to induce CD4+ T cells in allogeneic MLR, and thus resulting in a decreased ability of LC to promote CD4+ T cell proliferation and production of IFN-γ and IL-10. These data suggest that L3 exert a down-regulatory response in epidermal LC that leads to a diminished capacity of these cells to activate CD4+ T cells.

Filariasis in Travelers Presenting to the GeoSentinel Surveillance Network

Background As international travel increases, there is rising exposure to many pathogens not traditionally encountered in the resource-rich countries of the world. Filarial infections, a great problem throughout the tropics and subtropics, are relatively rare among travelers even to filaria-endemic regions of the world. The GeoSentinel Surveillance Network, a global network of medicine/travel clinics, was established in 1995 to detect morbidity trends among travelers. Principal Findings We examined data from the GeoSentinel database to determine demographic and travel characteristics associated with filaria acquisition and to understand the differences in clinical presentation between nonendemic visitors and those born in filaria-endemic regions of the world. Filarial infections comprised 0.62% (nu200a=u200a271) of all medical conditions reported to the GeoSentinel Network from travelers; 37% of patients were diagnosed with Onchocerca volvulus, 25% were infected with Loa loa, and another 25% were diagnosed with Wuchereria bancrofti. Most infections were reported from immigrants and from those immigrants returning to their county of origin (those visiting friends and relatives); the majority of filarial infections were acquired in sub-Saharan Africa. Among the patients who were natives of filaria-nonendemic regions, 70.6% acquired their filarial infection with exposure greater than 1 month. Moreover, nonendemic visitors to filaria-endemic regions were more likely to present to GeoSentinel sites with clinically symptomatic conditions compared with those who had lifelong exposure. Significance Codifying the filarial infections presenting to the GeoSentinel Surveillance Network has provided insights into the clinical differences seen among filaria-infected expatriates and those from endemic regions and demonstrated that O. volvulus infection can be acquired with short-term travel.

Onchocerciasis in a Nonendemic Population: Clinical and Immunologic Assessment before Treatment and at the Time of Presumed Cure

Although suppressive therapy for onchocerciasis with intermittent ivermectin prevents the development of pathology in endemic populations, the clinical and immunologic effects of therapy in the absence of continued exposure are unknown. To address this question, 14 patients treated with ivermectin for onchocerciasis acquired >10 years ago during temporary residence in Africa were reevaluated. None had evidence of continued infection or pathology at follow-up. Although eosinophilia, serum IgE, and antifilarial antibody levels decreased after ivermectin therapy, none of these parameters was useful in predicting the resolution of symptoms in infected patients. Peripheral blood mononuclear cells isolated from patients at follow-up were more responsive to parasite antigen in vitro, which is as assessed by proliferation and production of interferon-gamma and interleukin (IL)-5. In contrast, antigen-induced levels of IL-10 were significantly decreased at follow-up, consistent with diminished down-regulatory factors rather than a switch from type 2 to type 1 immune responses.

Quiescent Innate Response to Infective Filariae by Human Langerhans Cells Suggests a Strategy of Immune Evasion

ABSTRACT Filarial infection is initiated by mosquito-derived third-stage larvae (L3) deposited on the skin that transit through the epidermis, which contains Langerhans cells (LC) and keratinocytes (KC), among other cells. This earliest interaction between L3 and the LC likely conditions the priming of the immune system to the parasite. To determine the nature of this interaction, human LC (langerin+ E-cadherin+ CD1a+) were generated in vitro and exposed to live L3. LC exposed to live L3 for 48 h showed no alterations in the cell surface markers CD14, CD86, CD83, CD207, E-cadherin, CD80, CD40, and HLA-DR or in mRNA expression of inflammation-associated genes, such as those for interleukin 18 (IL-18), IL-18BP, and caspase 1. In contrast to L3, live tachyzoites of Toxoplasma gondii, an intracellular parasite, induced production of CXCL9, IP-10, and IL-6 in LC. Furthermore, preexposure of LC to L3 did not alter Toll-like receptor 3 (TLR3)- or TLR4-mediated expression of the proinflammatory cytokines IL-1β, gamma interferon (IFN-γ), IL-6, or IL-10. Interestingly, cocultures of KC and LC produced significantly more IL-18, IL-1α, and IL-8 than did cultures of LC alone, although exposure of the cocultures to live L3 did not result in altered cytokine production. Microarray examination of ex vivo LC from skin blisters that were exposed to live L3 also showed few significant changes in gene expression compared with unexposed blisters, further underscoring the relatively muted response of LC to L3. Our data suggest that failure by LC to initiate an inflammatory response to the invasive stage of filarial parasites may be a strategy for immune evasion by the filarial parasite.

Eosinophil-Associated Processes Underlie Differences in Clinical Presentation of Loiasis Between Temporary Residents and Those Indigenous to Loa-Endemic Areas

BACKGROUNDnLoa loa has emerged as an important public health problem due to the occurrence of immune-mediated severe posttreatment reactions following ivermectin distribution. Also thought to be immune-mediated are the dramatic differences seen in clinical presentation between infected temporary residents (TR) and individuals native to endemic regions (END).nnnMETHODSnAll patients diagnosed with loiasis at the National Institutes of Health between 1976 and 2012 were included. Patients enrolled in the study underwent a baseline clinical and laboratory evaluation and had serum collected and stored. Stored pretreatment serum was used to measure filaria-specific antibody responses, eosinophil-related cytokines, and eosinophil granule proteins.nnnRESULTSnLoa loa infection in TR was characterized by the presence of Calabar swelling (in 82% of subjects), markedly elevated eosinophil counts, and increased filaria-specific immunoglobulin G (IgG) levels; these findings were thought to reflect an unmodulated immune response. In contrast, END showed strong evidence for immune tolerance to the parasite, with high levels of circulating microfilariae, few clinical symptoms, and diminished filaria-specific IgG. The striking elevation in eosinophil counts among the TR group was accompanied by increased eosinophil granule protein levels (associated with eosinophil activation and degranulation) as well as elevated levels of eosinophil-associated cytokines.nnnCONCLUSIONSnThese data support the hypothesis that differing eosinophil-associated responses to the parasite may be responsible for the marked differences in clinical presentations between TR and END populations with loiasis.

Familial Hypereosinophilic Syndrome

Idiopathic hypereosinophilic syndrome (HES) is a heterogeneous group of disorders defined as peripheral eosinophilia of > 1500 eosinophils/ul for at least 6 months without discernible cause and the presence of eosinophil-related end-organ dysfunction [1,2]. HES occurs sporadically in the general population and is most common in men between the ages of 20 and 50 years [3]. End-organ dysfunction frequently involves the heart (myocarditis, cardiomyopathy, endomyocardial fibrosis), the nervous system (peripheral neuropathy, thromboembolism and encephalopathy), the skin (angioedema, urticaria, mucosal ulcerations) and the lungs (chronic cough, infiltrates, pulmonary fibrosis), although any organ can be affected.