an-vitro-model-for-measuring-immune-responses-to-malaria-context-hiv

An <em>In Vitro</em> Model for Measuring Immune Responses to Malaria in the Context of HIV Co-infection

Malaria and HIV co-infection is a growing health priority. However, most research on malaria or HIV currently focuses on each infection individually. ...

University of Calgary

Allergic diseases mediated by T helper type (Th) 2 cell immune responses are rising dramatically in most developed countries. Exaggerated Th2 cell reactivity could result, for example, from diminished exposure to Th1 cell-inducing microbial infections. Epidemiological studies, however, indicate that Th2 cell-stimulating helminth parasites may also counteract allergies, possibly by generating regulatory T cells which suppress both Th1 and Th2 arms of immunity. We therefore tested the ability of the Th2 cell-inducing gastrointestinal nematode Heligmosomoides polygyrus to influence experimentally induced airway allergy to ovalbumin and the house dust mite allergen Der p 1. Inflammatory cell infiltrates in the lung were suppressed in infected mice compared with uninfected controls. Suppression was reversed in mice treated with antibodies to CD25. Most notably, suppression was transferable with mesenteric lymph node cells (MLNC) from infected animals to uninfected sensitized mice, demonstrating that the effector phase was targeted. MLNC from infected animals contained elevated numbers of CD4(+)CD25(+)Foxp3(+) T cells, higher TGF-beta expression, and produced strong interleukin (IL)-10 responses to parasite antigen. However, MLNC from IL-10-deficient animals transferred suppression to sensitized hosts, indicating that IL-10 is not the primary modulator of the allergic response. Suppression was associated with CD4(+) T cells from MLNC, with the CD4(+)CD25(+) marker defining the most active population. These data support the contention that helminth infections elicit a regulatory T cell population able to down-regulate allergen induced lung pathology in vivo.

Suppression of allergic airway inflammation by helminth-induced regulatory T cells.

Regulatory T cell responses to infectious organisms influence not only immunity and immunopathology, but also responses to bystander antigens. Mice infected with the gastrointestinal nematode parasite Heligmosomoides polygyrus show an early Th2-dominated immune response (days 7-14), but by day 28 a strongly regulatory profile is evident with antigen-specific IL-10 release and elevated frequency of CD4(+) T cells bearing surface TGF-beta. CD4(+)CD25(+) T cells from infected mice show enhanced capacity to block in vitro effector T cell proliferation. CD4(+)CD25(+) cell numbers expand dramatically during infection, with parallel growth of both CD25(+)Foxp3(+) and CD25(+)Foxp3(-) subsets. CTLA-4 and glucocorticoid-induced tolerance-associated receptor, also associated with regulatory T cell function, become more prominent, due to both expanded CD25(+) cell numbers and increased expression among the CD25(-) population. Both intensity and frequency of CD103 expression by CD4(+) T cells rise significantly, with greatest expansion among CD25(+)Foxp3(+) cells. While TGF-beta expression is observed among both CD25(+)Foxp3(+) and CD25(+)Foxp3(-) subsets, it is the latter population which shows higher TGF-beta staining following infection. These data demonstrate in a chronic helminth infection that Foxp3(+) regulatory T cells are stimulated, increasing CD103 expression in particular, but that significant changes occur to other populations including expansion of CD25(+)TGF-beta(+)Foxp3(-) cells, and induction of CTLA-4 on CD25(-) non-regulatory lymphocytes.

Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection.

Severe forms of malaria infection claim over 1 million lives annually. One aspect of severe malaria pathogenesis is an excessive or dysregulated inflammatory response to infection. With the characterization of Toll-like receptors (TLRs), which initiate inflammation upon detection of microbial products, involvement of TLRs in the host response to malaria has undergone intense investigation. While TLRs appear to mediate inflammation in malaria infection and may contribute to development of severe malaria, it is unlikely that they operate in isolation from other components of innate immunity. Here, we highlight recent findings implicating other innate immune mechanisms in the host inflammatory response to malaria, propose how they may integrate and synergize with TLR pathways, and discuss opportunities and challenges associated with anti-inflammatory adjunctive therapy for the treatment of severe malaria.

Inflammatory pathways in malaria infection: TLRs share the stage with other components of innate immunity.

Placental malaria (PM) is a leading cause of maternal and infant mortality. Although the accumulation of parasitized erythrocytes (PEs) and monocytes within the placenta is thought to contribute to the pathophysiology of PM, the molecular mechanisms underlying PM remain unclear. Based on the hypothesis that excessive complement activation may contribute to PM, in particular generation of the potent inflammatory peptide C5a, we investigated the role of C5a in the pathogenesis of PM in vitro and in vivo.

C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria.

Le paludisme placentaire (PM) est des principales causes de mortalit&eacute; maternelle et infantile. Bien que l&#39;accumulation des &eacute;rythrocytes parasit&eacute;s (PEs) et les monocytes dans le placenta est pens&eacute;e pour contribuer &agrave; la physiopathologie de la PM, les m&eacute;canismes mol&eacute;culaires sous-jacents PM demeurent obscures. Bas&eacute; sur l&#39;hypoth&egrave;se que l&#39;activation du compl&eacute;ment excessive peut contribuer &agrave; PM, dans une g&eacute;n&eacute;ration particuli&egrave;re du puissant peptide inflammatoire C5a, nous avons &eacute;tudi&eacute; le r&ocirc;le de C5a dans la pathogen&egrave;se de la PM in vitro et in vivo.

C5a am&eacute;liore la dysr&eacute;gulation inflammatoire et r&eacute;ponses angiog&eacute;nique au paludisme in vitro : les implications potentielles pour le paludisme placentaire.

Plazenta Malaria (PM) ist eine f&uuml;hrende Ursache von Sterblichkeit von M&uuml;ttern und Kindern. Obwohl die Anh&auml;ufung von parasitized Erythrozyten (SPE) und Monozyten innerhalb der Plazenta Beitrag zur Pathophysiologie der PM gedacht ist, sind die molekularen Mechanismen PM noch unklar. Basierend auf der Hypothese, die &uuml;berm&auml;&szlig;ige Komplement-Aktivierung in bestimmten Generation potenter entz&uuml;ndliche Peptids C5a, Uhr, beitragen k&ouml;nnen untersucht wir die Rolle von C5a in der Pathogenese von PM in vitro und in vivo.

C5a verbessert die defekten entz&uuml;ndliche und angiogenen Reaktionen auf Malaria in-vitro: m&ouml;gliche Implikationen f&uuml;r Plazenta Malaria.

La malaria placenta (PM) &egrave; delle principali cause di mortalit&agrave; materna e infantile. Anche se l&#39;accumulo di eritrociti parassitati (PEs) e monociti all&#39;interno della placenta &egrave; pensato per contribuire alla fisiopatologia della PM, rimangono poco chiari i meccanismi molecolari sottostanti PM. Basato sull&#39;ipotesi che attivazione complemento eccessivo pu&ograve; contribuire al PM, in particolare generazione del potente peptide infiammatorio C5a, abbiamo studiato il ruolo di C5a nella patogenesi della PM in vitro e in vivo.

C5a aumenta infiammatoria e angiogenic responses to la malaria in vitro: potenziali implicazioni per la malaria placenta.

&#x80CE;&#x76D8;&#x759F;&#x75BE; &#xFF08;PM&#xFF09; &#x662F;&#x4EA7;&#x5987;&#x548C;&#x5A74;&#x513F;&#x6B7B;&#x4EA1;&#x7387;&#x7684;&#x4E00;&#x4E2A;&#x4E3B;&#x8981;&#x539F;&#x56E0;&#x3002;&#x867D;&#x7136;&#x8BA4;&#x4E3A;&#x662F;&#x5BC4;&#x751F;&#x7684;&#x7EA2;&#x7EC6;&#x80DE; (PEs) &#x548C;&#x5355;&#x6838;&#x7EC6;&#x80DE;&#x5728;&#x80CE;&#x76D8;&#x5185;&#x7684;&#x79EF;&#x7D2F;&#x4F5C;&#x51FA;&#x8D21;&#x732E;&#x7684;&#x4E0B;&#x5348;&#x75C5;&#x7406;&#x751F;&#x7406;&#x5B66;&#xFF0C;&#x57FA;&#x7840;&#x4E0B;&#x5348;&#x7684;&#x5206;&#x5B50;&#x673A;&#x5236;&#x4ECD;&#x4E0D;&#x6E05;&#x695A;&#x3002;&#x6211;&#x4EEC;&#x57FA;&#x4E8E;&#x8FD9;&#x4E2A;&#x5047;&#x8BBE;&#xFF0C;&#x8FC7;&#x5EA6;&#x8865;&#x4F53;&#x6FC0;&#x6D3B;&#x53EF;&#x80FD;&#x4E0B;&#x5348;&#xFF0C;&#x4F5C;&#x51FA;&#x8D21;&#x732E;&#xFF0C;&#x60C5;&#x51B5;&#x7279;&#x522B;&#x4EE3;&#x7684;&#x70C8;&#x6027;&#x708E;&#x75C7;&#x80BD; C5a&#xFF0C;&#x8C03;&#x67E5; C5a &#x7684;&#x4E0B;&#x5348;&#x5728;&#x4F53;&#x5916;&#x548C;&#x4F53;&#x5185;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x4E2D;&#x7684;&#x4F5C;&#x7528;&#x3002;

C5a &#x63D0;&#x9AD8;&#x6C34;&#x5E73;&#x53CA;&#x708E;&#x75C7;&#x548C;&#x759F;&#x75BE;&#x4F53;&#x5916;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x54CD;&#x5E94;&#xFF1A; &#x80CE;&#x76D8;&#x759F;&#x75BE;&#x7684;&#x6F5C;&#x5728;&#x5F71;&#x54CD;&#x3002;

&#x80CE;&#x76E4;&#x30DE;&#x30E9;&#x30EA;&#x30A2; &#xFF08;PM&#xFF09; &#x306F;&#x3001;&#x6BCD;&#x89AA;&#x3068;&#x4E73;&#x5150;&#x6B7B;&#x4EA1;&#x7387;&#x306E;&#x4E3B;&#x8981;&#x306A;&#x539F;&#x56E0;&#x3067;&#x3059;&#x3002;&#x5348;&#x5F8C;&#x306E;&#x75C5;&#x614B;&#x306B;&#x5BC4;&#x4E0E;&#x3059;&#x308B;&#x5BC4;&#x751F;&#x8D64;&#x8840;&#x7403; (PEs) &#x3068;&#x80CE;&#x76E4;&#x5185;&#x5358;&#x7403;&#x306E;&#x84C4;&#x7A4D;&#x3092;&#x8003;&#x3048;&#x3066;&#x3001;PM&#x3001;&#x5206;&#x5B50;&#x6A5F;&#x69CB;&#x306F;&#x4E0D;&#x660E;&#x3057;&#x307E;&#x3059;&#x3002;&#x904E;&#x5EA6;&#x306E;&#x88DC;&#x4F53;&#x6D3B;&#x6027;&#x5316;&#x5348;&#x5F8C;&#x306B;&#x306F;&#x3001;&#x5F37;&#x529B;&#x306A;&#x708E;&#x75C7;&#x6027;&#x30DA;&#x30D7;&#x30C1;&#x30C9; C5a&#x3001;&#x7279;&#x5B9A;&#x306E;&#x4E16;&#x4EE3;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x3068;&#x3044;&#x3046;&#x4EEE;&#x8AAC;&#x306B;&#x57FA;&#x3065;&#x3044;&#x3066; PM in vitro &#x304A;&#x3088;&#x3073; in vivo &#x306E;&#x75C5;&#x56E0;&#x306B;&#x304A;&#x3051;&#x308B; C5a &#x306E;&#x5F79;&#x5272;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;

C5a &#x6765;&#x3059;&#x708E;&#x75C7;&#x3084;&#x30DE;&#x30E9;&#x30EA;&#x30A2; in vitro &#x8840;&#x7BA1;&#x65B0;&#x751F;&#x30EC;&#x30B9;&#x30DD;&#x30F3;&#x30B9;&#x5F37;&#x5316;: &#x80CE;&#x76E4;&#x30DE;&#x30E9;&#x30EA;&#x30A2;&#x306E;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x5F71;&#x97FF;&#x3002;

Placental &#xB9D0;&#xB77C;&#xB9AC;&#xC544; (&#xC624;&#xD6C4;) &#xC0B0; &#xBAA8;&#xC640; &#xC720;&#xC544; &#xC0AC;&#xB9DD;&#xC758; &#xC8FC;&#xC694; &#xC6D0;&#xC778;&#xC785;&#xB2C8;&#xB2E4;. Parasitized &#xC801;&#xD608;&#xAD6C; (PEs) &#xBC0F; &#xD0DC; &#xBC18; &#xB0B4;&#xC758; monocytes&#xC758; &#xCD95;&#xC801; &#xC624;&#xD6C4;&#xC758; &#xC774;&#xC0C1;&#xC5D0; &#xAE30;&#xC5EC;&#xD560; &#xC0DD;&#xAC01; &#xD558;&#xC9C0;&#xB9CC; &#xAE30;&#xBCF8; &#xC624;&#xD6C4; &#xBD84;&#xC790; &#xBA54;&#xCEE4;&#xB2C8;&#xC998; &#xBD88;&#xBD84;&#xBA85; &#xB0A8;&#xC544; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xACFC;&#xB3C4; &#xD55C; &#xBCF4;&#xC644; &#xD65C;&#xC131;&#xD654; &#xC624;&#xD6C4;, C5a, &#xAC15;&#xB825;&#xD55C; &#xC5FC;&#xC99D; &#xC131; &#xD3A9; &#xD2F0; &#xB4DC;&#xC758; &#xD2B9;&#xC815; &#xC138;&#xB300;&#xC5D0; &#xAE30;&#xC5EC;&#xD560; &#xC218; &#xC788;&#xB294; &#xAC00;&#xC124;&#xC5D0; &#xB530;&#xB77C; &#xC6B0;&#xB9AC; &#xC0DD;&#xCCB4; &#xC678; &#xBC0F; &#xC0DD;&#xCCB4; &#xC870;&#xAC74; &#xC624;&#xD6C4; pathogenesis c5a&#xC758; &#xC5ED;&#xD560;&#xC744; &#xC870;&#xC0AC; &#xD588;&#xB2E4;.

C5a &#xD5A5;&#xC0C1; dysregulated &#xC5FC;&#xC99D; &#xBC0F; &#xC0DD;&#xCCB4; &#xC678;&#xC5D0;&#xC11C; &#xB9D0;&#xB77C;&#xB9AC;&#xC544; angiogenic &#xC751;&#xB2F5;: placental &#xB9D0;&#xB77C;&#xB9AC;&#xC544;&#xC5D0; &#xB300; &#xD55C; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xC601;&#xD5A5;.

Paludismo placentario (PM) es la principal causa de mortalidad materna e infantil. Aunque se piensa que la acumulaci&oacute;n de eritrocitos parasitados (PEs) y monocitos dentro de la placenta es contribuir a la fisiopatolog&iacute;a de la PM, los mecanismos moleculares subyacentes PM todav&iacute;a no est&aacute;n claros. Partiendo de la hip&oacute;tesis de que la activaci&oacute;n del complemento excesivo puede contribuir a la PM, en particular generaci&oacute;n del potente p&eacute;ptido inflamatorio C5a, investigamos el papel de C5a en la patogenesia de PM in vitro e in vivo.

C5a mejora dysregulated inflamatoria y angiog&eacute;nicos responses to la malaria in vitro: posibles implicaciones para el paludismo placentario.

The Apicomplexa are a group of phylogenetically related parasitic protists that include Plasmodium, Cryptosporidium, and Toxoplasma. Together they are a major global burden on human health and economics. To meet this challenge, several international consortia have generated vast amounts of sequence data for many of these parasites. Here, we exploit these data to perform a systematic analysis of protein family and domain incidence across the phylum. A total of 87,736 protein sequences were collected from 15 apicomplexan species. These were compared with three protein databases, including the partial genome database, PartiGeneDB, which increases the breadth of taxonomic coverage. From these searches we constructed taxonomic profiles that reveal the extent of apicomplexan sequence diversity. Sequences without a significant match outside the phylum were denoted as apicomplexan specialized. These were collated into 9134 discrete protein families and placed in the context of the apicomplexan phylogeny, identifying the putative origin of each family. Most apicomplexan families were associated with an individual genus or species. Interestingly, many genera-specific innovations were associated with specialized host cell invasion and/or parasite survival processes. Contrastingly, those families reflecting more ancestral relationships were enriched in generalized housekeeping functions such as translation and transcription, which have diverged within the apicomplexan lineage. Protein domain searches revealed 192 domains not previously reported in apicomplexans together with a number of novel domain combinations. We highlight domains that may be important to parasite survival.

The origins of apicomplexan sequence innovation.

Research relating to host inflammatory processes during malaria infection has focused on Toll-like receptors, membrane-bound receptors implicated in innate sensing, and phagocytosis of parasitized erythrocytes by host cells. This is the first study to examine the role of Nod proteins, members of the Nod-like receptor (NLR) family of cytoplasmic proteins involved in pathogen recognition, in a murine model of cerebral malaria (Plasmodium berghei ANKA, PbA). Here, we find that nod1nod2(-/-) mice infected with PbA show no difference in survival or parasitemia compared with wild-type infected animals. However, cytokine levels, notably those associated with NLR activation including interleukin (IL)1-beta, KC, and MCP-1, and proteins linked to malaria pathogenesis, such as interferon-gamma (IFN-gamma), were decreased in the nod-1nod2(-/-) animals. We therefore demonstrate for the first time that Nod proteins are activated in response to parasites, and they play a role in regulating host inflammatory responses during malaria infection.

Disruption of Nod-like receptors alters inflammatory response to infection but does not confer protection in experimental cerebral malaria.

Severe malaria represents a clinical spectrum of disease. We propose that innate immune inflammatory responses to malaria play key roles in the pathogenesis and clinical outcomes of distinct severe malaria syndromes. To investigate this hypothesis, mice deficient in IRAK4, central to Toll-like receptor (TLR)-mediated signaling, were studied in two experimental models of malaria: Plasmodium berghei (PbA) and Plasmodium chabaudi (PccAS). Irak4(-/-)mice had decreased pro-inflammatory cytokine production during infection in both models. However, animals were relatively protected from PbA-associated symptoms compared with wild-type mice, whereas Irak4(-/-) animals were more susceptible to PccAS-associated disease. These results show that IRAK4-mediated innate immune inflammatory responses play critical roles in divergent clinical outcomes in murine malaria models. As such, integrated approaches, using more than one model, are required to fully understand the parasite/host interactions that characterize severe malaria, and more importantly, to fully assess the effect of adjunctive therapies targeting innate immune responses to malaria.

Divergent roles of IRAK4-mediated innate immune responses in two experimental models of severe malaria.

Foxp3-expressing regulatory T (T reg) cells have been implicated in parasite-driven inhibition of host immunity during chronic infection. We addressed whether parasites can directly induce T reg cells. Foxp3 expression was stimulated in naive Foxp3⁻ T cells in mice infected with the intestinal helminth Heligmosomoides polygyrus. In vitro, parasite-secreted proteins (termed H. polygyrus excretory-secretory antigen [HES]) induced de novo Foxp3 expression in fluorescence-sorted Foxp3⁻ splenocytes from Foxp3-green fluorescent protein reporter mice. HES-induced T reg cells suppressed both in vitro effector cell proliferation and in vivo allergic airway inflammation. HES ligated the transforming growth factor (TGF) β receptor and promoted Smad2/3 phosphorylation. Foxp3 induction by HES was lost in dominant-negative TGF-βRII cells and was abolished by the TGF-β signaling inhibitor SB431542. This inhibitor also reduced worm burdens in H. polygyrus-infected mice. HES induced IL-17 in the presence of IL-6 but did not promote Th1 or Th2 development under any conditions. Importantly, antibody to mammalian TGF-β did not recognize HES, whereas antisera that inhibited HES did not affect TGF-β. Foxp3 was also induced by secreted products of Teladorsagia circumcincta, a related nematode which is widespread in ruminant animals. We have therefore identified a novel pathway through which helminth parasites may stimulate T reg cells, which is likely to be a key part of the parasite's immunological relationship with the host.

Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway.

Pathogen sensing by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. Caspase-12 antagonizes the inflammasome and NF-κB and is associated with susceptibility to bacterial sepsis. A single-nucleotide polymorphism (T(125)C) in human Casp12 restricts its expression to Africa, Southeast Asia, and South America. Here, we investigated the role of caspase-12 in the control of parasite replication and pathogenesis in malaria and report that caspase-12 dampened parasite clearance in blood-stage malaria and modulated susceptibility to cerebral malaria. This response was independent of the caspase-1 inflammasome, as casp1(-/-) mice were indistinguishable from wild-type animals in response to malaria, but dependent on enhanced NF-κB activation. Mechanistically, caspase-12 competed with NEMO for association with IκB kinase-α/β, effectively preventing the formation of the IκB kinase complex and inhibiting downstream transcriptional activation by NF-κB. Systemic inhibition of NF-κB or Ab neutralization of IFN-γ reversed the increased resistance of casp12(-/-) mice to blood-stage malaria infection.

Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling.

Members of the CD36 scavenger receptor family have been implicated as sensors of microbial products that mediate phagocytosis and inflammation in response to a broad range of pathogens. We investigated the role of CD36 in host response to mycobacterial infection.

CD36 deficiency attenuates experimental mycobacterial infection.

Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL)(-/-) mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4(+) and CD8(+) T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.

S1P is associated with protection in human and experimental cerebral malaria.

Malaria and HIV-1 adversely interact, with HIV-positive individuals suffering higher parasite burdens and worse clinical outcomes. However, the mechanisms underlying these disease interactions are unclear. We hypothesized that HIV coinfection impairs the innate immune response to malaria, and that combination antiretroviral therapy (cART) may restore this response. Our aim was to examine the innate inflammatory response of natural killer (NK), natural killer T (NKT), and Î³Î´ T-cells isolated from the peripheral blood of HIV-infected therapy-naive donors to malaria parasites, and determine the effect of cART on these responses.

HIV infection deregulates innate immunity to malaria despite combination antiretroviral therapy.

The Tim-3 receptor has been implicated as a negative regulator of adaptive immune responses and has been linked to T-cell dysfunction in chronic viral infections, such as HIV. Blocking Tim-3 has been proposed as a potential therapeutic intervention in HIV infection. However, a more detailed characterization of Tim-3 expression in the presence of HIV is required before such strategies can be considered.

HIV infection deregulates Tim-3 expression on innate cells: combination antiretroviral therapy results in partial restoration.

Malaria-specific immune responses are altered in HIV/malaria-coinfected individuals and are associated with higher parasite burdens and more severe clinical disease. Monocyte/macrophage phagocytosis is a major mechanism of malaria parasite clearance. We hypothesized that phagocytosis of malaria-parasitized erythrocytes is impaired in coinfected individuals and could contribute to the increased parasite burdens observed. We show that nonopsonic phagocytosis of Plasmodium falciparum parasitized erythrocytes is impaired in monocytes isolated from HIV-infected individuals. The observed defects in phagocytic capacity were rescued after 6 months of antiretroviral therapy, demonstrating the importance of HIV treatment and immune reconstitution in the context of coinfection.

Chronic HIV infection impairs nonopsonic phagocytosis of malaria parasites.

The impact of the microbiota on the immune status of its host is a source of intense research and publicity. In comparison, the effect of arthropod microbiota on vector-borne infectious diseases has received little attention. A better understanding of the vector microbiota in relation to mammalian host immune responses is vital, as it can lead to strategies that affect transmission and improve vaccine design in a field of research where few vaccines exist and effective treatment is rare. Recent demonstrations of how microbiota decrease pathogen development in arthropods, and thus alter vector permissiveness to vector-borne diseases (VBDs), have led to renewed interest. However, hypotheses on the interactions between the arthropod-derived microbiota and the mammalian hosts have yet to be addressed. Advances in DNA sequencing technology, increased yield and falling costs, mean that these studies are now feasible for many microbiologists and entomologists. Here, we distill current knowledge and put forward key questions and experimental designs to shed light on this burgeoning research topic.

Article	Year
Suppression of allergic airway inflammation by helminth-induced regulatory T cells. The Journal of experimental medicine\| PubMed ID: 16275759	2005
Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection. European journal of immunology\| PubMed ID: 17563918	2007
Inflammatory pathways in malaria infection: TLRs share the stage with other components of innate immunity. Molecular and biochemical parasitology\| PubMed ID: 18804125	2008
C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria. PloS one\| PubMed ID: 19308263	2009
The origins of apicomplexan sequence innovation. Genome research\| PubMed ID: 19363216	2009
Disruption of Nod-like receptors alters inflammatory response to infection but does not confer protection in experimental cerebral malaria. The American journal of tropical medicine and hygiene\| PubMed ID: 19407112	2009
Divergent roles of IRAK4-mediated innate immune responses in two experimental models of severe malaria. The American journal of tropical medicine and hygiene\| PubMed ID: 20595480	2010
Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway. The Journal of experimental medicine\| PubMed ID: 20876311	2010
Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 20876354	2010
CD36 deficiency attenuates experimental mycobacterial infection. BMC infectious diseases\| PubMed ID: 20950462	2010
S1P is associated with protection in human and experimental cerebral malaria. Molecular medicine (Cambridge, Mass.)\| PubMed ID: 21556483	2011
HIV infection deregulates innate immunity to malaria despite combination antiretroviral therapy. AIDS (London, England)\| PubMed ID: 23291537	2013
HIV infection deregulates Tim-3 expression on innate cells: combination antiretroviral therapy results in partial restoration. Journal of acquired immune deficiency syndromes (1999)\| PubMed ID: 23314411	2013
Chronic HIV infection impairs nonopsonic phagocytosis of malaria parasites. Journal of acquired immune deficiency syndromes (1999)\| PubMed ID: 25415293	2015
Does the arthropod microbiota impact the establishment of vector-borne diseases in mammalian hosts? PLoS pathogens\| PubMed ID: 25856431	2015

Constance Finney

Biography

JoVE Journal Publications

Other Publications