Vector competence of Culex mosquitoes (Diptera: Culicidae) in Zika virus transmission: an integrative review.

OBJECTIVE: To identify studies on the competence of Culex mosquitoes as vectors for the transmission of Zika virus (ZIKV) around the globe. METHODS: We performed an integrative review to identify relevant articles on specific experiments to determine whether Culex mosquitoes are vectors for ZIKV. The sources we used for our research were the Brazilian Periódicos CAPES electronic portal (MEDLINE/PubMed, ScienceDirect Journals, Nature Publishing Group, SciELO, Springer Link, and 250 other databases) and gray literature. RESULTS: We identified 344 studies, of which 36 were considered for this review. In 8 studies, infection in salivary glands of Culex quinquefasciatus, Culex restuans, Culex tarsalis, and Culex coronator was detected. Cx. quinquefasciatus was the most studied among those confirmed as potential ZIKV vectors, and only strains of Asian lineages (THA/2014/SV0127-14; SZ01 (2016)) and American lineages (BRPE243 (2015); PRVABC59 (2015)) can infect the salivary glands of Culex mosquitoes. The tested African strains (MR766 and DAK AR 41525) were unable to infect salivary glands. CONCLUSIONS: There is still a lack of compelling evidence that indicates Culex spp. are a competent ZIKV vector, but they should remain a target for further monitoring studies, especially regarding ZIKV transmission to other species. Furthermore, studies should not be limited to studying whether their salivary glands are infected.

Vector competence of Culex mosquitoes (Diptera: Culicidae) in Zika virus transmission: an integrative review

[ABSTRACT]. Objective. To identify studies on the competence of Culex mosquitoes as vectors for the transmission of Zika virus (ZIKV) around the globe. Methods. We performed an integrative review to identify relevant articles on specific experiments to determine whether Culex mosquitoes are vectors for ZIKV. The sources we used for our research were the Brazilian Periódicos CAPES electronic portal (MEDLINE/PubMed, ScienceDirect Journals, Nature Publishing Group, SciELO, Springer Link, and 250 other databases) and gray literature. Results. We identified 344 studies, of which 36 were considered for this review. In 8 studies, infection in salivary glands of Culex quinquefasciatus, Culex restuans, Culex tarsalis, and Culex coronator was detected. Cx. quinquefasciatus was the most studied among those confirmed as potential ZIKV vectors, and only strains of Asian lineages (THA/2014/SV0127-14; SZ01 (2016)) and American lineages (BRPE243 (2015); PRVABC59 (2015)) can infect the salivary glands of Culex mosquitoes. The tested African strains (MR766 and DAK AR 41525) were unable to infect salivary glands. Conclusions. There is still a lack of compelling evidence that indicates Culex spp. are a competent ZIKV vector, but they should remain a target for further monitoring studies, especially regarding ZIKV transmission to other species. Furthermore, studies should not be limited to studying whether their salivary glands are infected.

[RESUMEN]. Objetivo. Identificar estudios sobre la competencia de los mosquitos Culex como vectores de la transmisión del virus del Zika en todo el mundo. Métodos. Se realizó una revisión integradora para identificar artículos relevantes sobre experimentos específicos dirigidos a determinar si los mosquitos Culex son vectores del virus del Zika. Se emplearon fuentes obtenidas a partir del portal electrónico de revistas CAPES (MEDLINE/PubMed, ScienceDirect Journals, Nature Publishing Group, SciELO, Springer Link, y otras 250 bases de datos) y la literatura gris. Resultados. Se identificaron 344 estudios, 36 de los cuales fueron considerados para esta revisión. En 8 estudios se detectó infección en las glándulas salivales de Culex quinquefasciatus, Culex restuans, Culex tarsalis y Culex coronator. Cx. quinquefasciatus fue la especie más estudiada entre las confirmadas como potenciales vectores del virus del Zika, y solo las cepas de linajes asiáticos (THA/2014/SV0127-14; SZ01 [2016]) y americanos (BRPE243 [2015]; PRVABC59 [2015]) pueden infectar las glándulas salivales de los mosquitos Culex. Las cepas africanas analizadas (MR766 y DAK AR 41525) no fueron capaces de infectar las glándulas salivales. Conclusiones. Aunque faltan pruebas convincentes que indiquen que las especies de Culex spp. son un vector competente del virus del Zika, estas deben seguir monitoreándose mediante estudios adicionales, especialmente respecto de su capacidad para transmitir el virus del Zika a otras especies. Esta vigilancia no debería limitarse solamente a determinar la infección en las glándulas salivales.

[RESUMO]. Objetivo. Identificar estudos sobre a competência dos mosquitos Culex como vetores da transmissão do vírus Zika em todo o mundo. Métodos. Uma revisão integrativa foi realizada para identificar artigos relevantes sobre experimentos específicos para determinar se os mosquitos Culex são vetores do vírus Zika. As fontes utilizadas na pesquisa foram o portal eletrônico CAPES (MEDLINE/PubMed, ScienceDirect Journals, Nature Publishing Group, Sci-ELO, Springer Link, e outras 250 bases de dados) e a literatura cinza. Resultados. Foram identificados 344 artigos, dos quais 36 foram considerados para esta revisão. Oito artigos relataram infecção nas glândulas salivares de Culex quinquefasciatus, Culex restuans, Culex tarsalis e Culex coronator. Culex quinquefasciatus foi a espécie mais estudada entre as confirmadas como vetores potenciais do vírus Zika. Apenas as linhagens asiáticas (THA / 2014 / SV0127-14; SZ01 [2016]) e americanas (BRPE243 [2015]; PRVABC59 [2015]) podem infectar as glândulas salivares dos mosquitos Culex. As cepas africanas analisadas (MR766 e DAK AR 41525) não foram capazes de infectar as glândulas salivares. Conclusões. Ainda não há evidências convincentes para indicar que os mosquitos Culex são um vetor competente do vírus Zika. Contudo, estudos adicionais de monitoramento devem ser realizados, especialmente no que diz respeito à transmissão do vírus Zika para outras espécies de mosquitos. Além disso, os estudos não devem se limitar a estudar a infecção nas glândulas salivares.

Vector competence of Culex mosquitoes (Diptera: Culicidae) in Zika virus transmission: an integrative review / Competencia de los mosquitos Culex (Diptera: Culicidae) como vectores en la transmisión del virus del Zika: una revisión integradora / Competência vetorial de mosquitos Culex (Diptera: Culicidae) na transmissão do vírus Zika: revisão integrativa

ABSTRACT Objective. To identify studies on the competence of Culex mosquitoes as vectors for the transmission of Zika virus (ZIKV) around the globe. Methods. We performed an integrative review to identify relevant articles on specific experiments to determine whether Culex mosquitoes are vectors for ZIKV. The sources we used for our research were the Brazilian Periódicos CAPES electronic portal (MEDLINE/PubMed, ScienceDirect Journals, Nature Publishing Group, SciELO, Springer Link, and 250 other databases) and gray literature. Results. We identified 344 studies, of which 36 were considered for this review. In 8 studies, infection in salivary glands of Culex quinquefasciatus, Culex restuans, Culex tarsalis, and Culex coronator was detected. Cx. quinquefasciatus was the most studied among those confirmed as potential ZIKV vectors, and only strains of Asian lineages (THA/2014/SV0127-14; SZ01 (2016)) and American lineages (BRPE243 (2015); PRVABC59 (2015)) can infect the salivary glands of Culex mosquitoes. The tested African strains (MR766 and DAK AR 41525) were unable to infect salivary glands. Conclusions. There is still a lack of compelling evidence that indicates Culex spp. are a competent ZIKV vector, but they should remain a target for further monitoring studies, especially regarding ZIKV transmission to other species. Furthermore, studies should not be limited to studying whether their salivary glands are infected.(AU)

RESUMEN Objetivo. Identificar estudios sobre la competencia de los mosquitos Culex como vectores de la transmisión del virus del Zika en todo el mundo. Métodos. Se realizó una revisión integradora para identificar artículos relevantes sobre experimentos específicos dirigidos a determinar si los mosquitos Culex son vectores del virus del Zika. Se emplearon fuentes obtenidas a partir del portal electrónico de revistas CAPES (MEDLINE/PubMed, ScienceDirect Journals, Nature Publishing Group, SciELO, Springer Link, y otras 250 bases de datos) y la literatura gris. Resultados. Se identificaron 344 estudios, 36 de los cuales fueron considerados para esta revisión. En 8 estudios se detectó infección en las glándulas salivales de Culex quinquefasciatus, Culex restuans, Culex tarsalis y Culex coronator. Cx. quinquefasciatus fue la especie más estudiada entre las confirmadas como potenciales vectores del virus del Zika, y solo las cepas de linajes asiáticos (THA/2014/SV0127-14; SZ01 [2016]) y americanos (BRPE243 [2015]; PRVABC59 [2015]) pueden infectar las glándulas salivales de los mosquitos Culex. Las cepas africanas analizadas (MR766 y DAK AR 41525) no fueron capaces de infectar las glándulas salivales. Conclusiones. Aunque faltan pruebas convincentes que indiquen que las especies de Culex spp. son un vector competente del virus del Zika, estas deben seguir monitoreándose mediante estudios adicionales, especialmente respecto de su capacidad para transmitir el virus del Zika a otras especies. Esta vigilancia no debería limitarse solamente a determinar la infección en las glándulas salivales.(AU)

RESUMO Objetivo. Identificar estudos sobre a competência dos mosquitos Culex como vetores da transmissão do vírus Zika em todo o mundo. Métodos. Uma revisão integrativa foi realizada para identificar artigos relevantes sobre experimentos específicos para determinar se os mosquitos Culex são vetores do vírus Zika. As fontes utilizadas na pesquisa foram o portal eletrônico CAPES (MEDLINE/PubMed, ScienceDirect Journals, Nature Publishing Group, Sci-ELO, Springer Link, e outras 250 bases de dados) e a literatura cinza. Resultados. Foram identificados 344 artigos, dos quais 36 foram considerados para esta revisão. Oito artigos relataram infecção nas glândulas salivares de Culex quinquefasciatus, Culex restuans, Culex tarsalis e Culex coronator. Culex quinquefasciatus foi a espécie mais estudada entre as confirmadas como vetores potenciais do vírus Zika. Apenas as linhagens asiáticas (THA / 2014 / SV0127-14; SZ01 [2016]) e americanas (BRPE243 [2015]; PRVABC59 [2015]) podem infectar as glândulas salivares dos mosquitos Culex. As cepas africanas analisadas (MR766 e DAK AR 41525) não foram capazes de infectar as glândulas salivares. Conclusões. Ainda não há evidências convincentes para indicar que os mosquitos Culex são um vetor competente do vírus Zika. Contudo, estudos adicionais de monitoramento devem ser realizados, especialmente no que diz respeito à transmissão do vírus Zika para outras espécies de mosquitos. Além disso, os estudos não devem se limitar a estudar a infecção nas glândulas salivares.(AU)

IL-27 enhances Leishmania amazonensis infection via ds-RNA dependent kinase (PKR) and IL-10 signaling.

The protozoan parasite Leishmania infects and replicates in macrophages, causing a spectrum of diseases in the human host, varying from cutaneous to visceral clinical forms. It is known that cytokines modulate the immunological response against Leishmania and are relevant for infection resolution. Here, we report that Interleukin (IL)-27 increases Leishmania amazonensis replication in human and murine macrophages and that the blockage of the IL-10 receptor on the surface of infected cells abolished the IL-27-mediated enhancement of Leishmania growth. IL-27 induced the activation/phosphorylation of protein kinase R (PKR) in macrophages, and PKR blockage or PKR gene deletion abrogated the enhancement of the parasite growth driven by IL-27, as well as the L. amazonensis-induced macrophage production of IL-27. We also observed that L. amazonensis-induced expression of IL-27 depends on type I interferon signaling and the engagement of Toll-like receptor 2. Treatment of Leishmania-infected mice with IL-27 increased lesion size and parasite loads in the footpad and lymph nodes of infected animals, indicating that this cytokine exerts a local and a systemic effect on parasite growth and propagation. In conclusion, we show that IL-27 is a L. amazonensis-enhancing factor and that the PKR/IFN1 axis and IL-10 are critical mediators of this IL-27 induced effect.

Macrophage Resistance to HIV-1 Infection Is Enhanced by the Neuropeptides VIP and PACAP.

It is well established that host factors can modulate HIV-1 replication in macrophages, critical cells in the pathogenesis of HIV-1 infection due to their ability to continuously produce virus. The neuropeptides VIP and PACAP induce well-characterized effects on macrophages through binding to the G protein-coupled receptors VPAC1, VPAC2 and PAC1, but their influence on HIV-1 production by these cells has not been established. Here, we describe that VIP and PACAP reduce macrophage production of HIV-1, acting in a synergistic or additive manner to decrease viral growth. Using receptor antagonists, we detected that the HIV-1 inhibition promoted by VIP is dependent on its ligation to VPAC1/2, whereas PACAP decreases HIV-1 growth via activation of the VPAC1/2 and PAC1 receptors. Specific agonists of VPAC2 or PAC1 decrease macrophage production of HIV-1, whereas sole activation of VPAC1 enhances viral growth. However, the combination of specific agonists mimicking the receptor preference of the natural neuropeptides reproduces the ability of VIP and PACAP to increase macrophage resistance to HIV-1 replication. VIP and PACAP up-regulated macrophage secretion of the ß-chemokines CCL3 and CCL5 and the cytokine IL-10, whose neutralization reversed the neuropeptide-induced inhibition of HIV-1 replication. Our results suggest that VIP and PACAP and the receptors VPAC2 and PAC1 could be used as targets for developing alternative therapeutic strategies for HIV-1 infection.

Microbial translocation induces an intense proinflammatory response in patients with visceral leishmaniasis and HIV type 1 coinfection.

BACKGROUND: Leishmania infection is a cofactor in the heightened cellular activation observed in patients with American visceral leishmaniasis and human immunodeficiency virus type 1 (HIV) infection, with or without progression to AIDS (AVL/HIV). Thus, the persistence of a high parasite load despite antileishmanial therapy could be responsible for the continued immune stimulation. METHODS: CD8(+) T cells expressing CD38, parasite load, lipopolysaccharide (LPS), soluble CD14, macrophage migration inhibitory factor (MIF), intestinal fatty acid-binding protein (IFABP), and proinflammatory cytokines (interleukin 1ß, interleukin 6, interleukin 8, interleukin 17, interferon γ, and tumor necrosis factor) were measured in 17 patients with AVL/HIV, 16 with HIV, and 14 healthy subjects (HS). RESULTS: Lower Leishmania parasitemia was observed after antileishmanial and antiretroviral therapies. However, higher levels of CD38(+) on CD8(+) T cells were observed in both clinical phases of leishmaniasis, compared with HIV cases. AVL/HIV and HIV patients showed higher levels of LPS and IFABP than HS. Proinflammatory cytokine levels were significantly augmented in patients with active coinfection, as well as those with remission of Leishmania infection. LPS levels and Leishmania infection were positively correlated with CD38 expression on CD8(+) T cells and with IL-6 and IL-8 levels. CONCLUSIONS: LPS levels along with the immune consequences of Leishmania infection were associated with elevated cellular activation in coinfected patients. As a consequence, secondary chemoprophylaxis for leishmaniasis or even the use of antiinflammatory drugs or antibiotics may be considered for improving the prognosis of AVL/HIV.

Evidence that lipopolisaccharide may contribute to the cytokine storm and cellular activation in patients with visceral leishmaniasis.

BACKGROUND: Visceral leishmaniasis (VL) is characterized by parasite-specific immunosuppression besides an intense pro-inflammatory response. Lipopolisaccharide (LPS) has been implicated in the immune activation of T-cell deficient diseases such as HIV/AIDS and idiopathic lymphocytopenia. The source of LPS is gram-negative bacteria that enter the circulation because of immunological mucosal barrier breakdown. As gut parasitization also occurs in VL, it was hypothesized that LPS may be elevated in leishmaniasis, contributing to cell activation. METHODOLOGY/PRINCIPAL FINDINGS: Flow cytometry analysis and immunoassays (ELISA and luminex micro-beads system) were used to quantify T-cells and soluble factors. Higher LPS and soluble CD14 levels were observed in active VL in comparison to healthy subjects, indicating that LPS was bioactive; there was a positive correlation between these molecules (r = 0.61;p<0.05). Interestingly, LPS was negatively correlated with CD4(+) (r = -0.71;p<0.01) and CD8(+) T-cells (r = -0.65;p<0.05). Moreover, higher levels of activation-associated molecules (HLA-DR, CD38, CD25) were seen on T lymphocytes, which were positively associated with LPS levels. Pro-inflammatory cytokines and macrophage migration inhibitory factor (MIF) were also augmented in VL patients. Consistent with the higher immune activation status, LPS levels were positively correlated with the inflammatory cytokines IL-6 (r = 0.63;p<0.05), IL-8 (r = 0.89;p<0.05), and MIF (r = 0.64;p<0.05). Also, higher plasma intestinal fatty acid binding protein (IFABP) levels were observed in VL patients, which correlated with LPS levels (r = 0.57;p<0.05). CONCLUSIONS/SIGNIFICANCE: Elevated levels of LPS in VL, in correlation with T-cell activation and elevated pro-inflammatory cytokines and MIF indicate that this bacterial product may contribute to the impairment in immune effector function. The cytokine storm and chronic immune hyperactivation status may contribute to the observed T-cell depletion. LPS probably originates from microbial translocation as suggested by IFABP levels and, along with Leishmania antigen-mediated immune suppression, may play a role in the immunopathogenesis of VL. These findings point to possible benefits of antimicrobial prophylaxis in conjunction with anti-Leishmania therapy.

Elevated levels of macrophage migration inhibitory factor (MIF) in the plasma of HIV-1-infected patients and in HIV-1-infected cell cultures: a relevant role on viral replication.

The cytokine macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of inflammatory and infectious diseases, however its role in HIV-1 infection is unknown. Here we show that HIV-1-infected patients present elevated plasma levels of MIF, that HIV-1-infected peripheral blood mononuclear cells (PBMCs) release a greater amount of MIF, and that the HIV-1 envelope glycoprotein gp120 induces MIF secretion from uninfected PBMCs. The HIV-1 replication in PBMCs declines when these cells are treated with anti-MIF antibodies, and exposure of HIV-1-infected cells to the ABC-transporter inhibitor probenecid results in inhibition of MIF secretion. The addition of recombinant MIF (rhMIF) to HIV-1-infected PBMCs enhances viral replication of CCR5- or CXCR4-tropic HIV-1 isolates. Using a T CD4(+) cell lineage containing an HIV long terminal repeats (LTR)-Luciferase construct, we detected that rhMIF promotes transcription from HIV-1 LTR. Our results show that HIV-1 induces MIF secretion and suggest that MIF influences the HIV-1 biology through activation of HIV-1 LTR.