Novel role for the double‐stranded RNA‐activated protein kinase PKR: modulation of macrophage infection by the protozoan parasite<i>Leishmania</i>

Pereira, Renata M.; Teixeira, Karina Luiza Dias; Barreto-de-Souza, Victor; Calegari-Silva, Teresa Cristina; Melo, Luiz Dione Barbosa de; Soares, Deivid Costa; Bou-Habib, Dumith Chequer; Silva, Aristóbolo M.; Saraiva, Elvira M.; Lopes, Ulisses Gazos

doi:10.1096/fj.09-140053

Cited by 51 publications

(75 citation statements)

References 48 publications

(53 reference statements)

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“…Despite the fact that type I IFNs are mainly known for their antiviral role, increasing evidence attests to the involvement of type I IFNs in bacterial and parasitic infection (24)(25)(26)(27)29). Our findings are consistent with earlier reports suggestive of a disease-exacerbatory role for type I interferons in New World Leishmania species (33)(34)(35).…”

Section: Discussionsupporting

confidence: 92%

“…During parasite infection, type I IFNs show more variable effects, being either protective or detrimental for the host, depending on the dose, timing of administration, and the parasite species (28,29). For L. major, type I IFNs have been associated with control (30)(31)(32), whereas for other species, especially the New World species L. amazonensis and L. braziliensis, IFN-β has been associated with promotion of parasite survival and/or disease (33)(34)(35).…”

mentioning

confidence: 99%

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Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

Rossi

Castiglioni

Hartley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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The presence of the endogenous Leishmania RNA virus 1 (LRV1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. Here, we show that the disease-exacerbatory role of LRV1 relies on type I IFN (type I IFNs) production by macrophages and signaling in vivo. Moreover, infecting mice with the LRV1-cured Leishmania guyanensis (LgyLRV1 − ) strain of parasites followed by type I IFN treatment increased lesion size and parasite burden, quantitatively reproducing the LRV1-bearing (LgyLRV1 + ) infection phenotype. This finding suggested the possibility that exogenous viral infections could likewise increase pathogenicity, which was tested by coinfecting mice with L. guyanensis and lymphocytic choriomeningitis virus (LCMV), or the sand fly-transmitted arbovirus Toscana virus (TOSV). The type I IFN antiviral response increased the pathology of L. guyanensis infection, accompanied by down-regulation of the IFN-γ receptor normally required for antileishmanial control. Further, LCMV coinfection of IFN-γ-deficient mice promoted parasite dissemination to secondary sites, reproducing the LgyLRV1 + metastatic phenotype. Remarkably, LCMV coinfection of mice that had healed from L. guyanensis infection induced reactivation of disease pathology, overriding the protective adaptive immune response. Our findings establish that type I IFN-dependent responses, arising from endogenous viral elements (dsRNA/LRV1), or exogenous coinfection with IFN-inducing viruses, are able to synergize with New World Leishmania parasites in both primary and relapse infections. Thus, viral infections likely represent a significant risk factor along with parasite and host factors, thereby contributing to the pathological spectrum of human leishmaniasis.Leishmania RNA virus 1 | Totiviridae | arboviruses | trypanosomatid protozoan parasite | Leishmania subgenus Viannia

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

Rossi

Castiglioni

Hartley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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“…PKR is known to have antiviral properties due to its role in translational control. However, a possible role of PKR in protozoan parasitic infection (Leishmania) has been reported recently (41). The observation of an association between Toxoplasma infection and PKR has not been reported previously.…”

Section: Significant Transcript Changes Specific To Type I Infectionmentioning

confidence: 96%

Differential Effects of Three CanonicalToxoplasmaStrains on Gene Expression in Human Neuroepithelial Cells

Xiao¹,

Jones‐Brando²,

Talbot³

et al. 2011

Infect Immun

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Strain type is one of the key factors suspected to play a role in determining the outcome of Toxoplasma infection. In this study, we examined the transcriptional profile of human neuroepithelioma cells in response to representative strains of Toxoplasma by using microarray analysis to characterize the strain-specific host cell response. The study of neural cells is of interest in light of the ability of Toxoplasma to infect the brain and to establish persistent infection within the central nervous system. We found that the extents of the expression changes varied considerably among the three strains. Neuroepithelial cells infected with Toxoplasma type I exhibited the highest level of differential gene expression, whereas type II-infected cells had a substantially smaller number of genes which were differentially expressed. Cells infected with type III exhibited intermediate effects on gene expression. The three strains also differed in the individual genes and gene pathways which were altered following cellular infection. For example, gene ontology (GO) analysis indicated that type I infection largely affects genes related to the central nervous system, while type III infection largely alters genes which affect nucleotide metabolism; type II infection does not alter the expression of a clearly defined set of genes. Moreover, Ingenuity Pathways Analysis (IPA) suggests that the three lineages differ in the ability to manipulate their host; e.g., they employ different strategies to avoid, deflect, or subvert host defense mechanisms. These observed differences may explain some of the variation in the neurobiological effects of different strains of Toxoplasma on infected individuals.

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“…The region showing the highest excessive European ancestry is located on 3q13, which only harbors LSAMP, a candidate of the tumor suppressor gene in human osteosarcomas, and is associated with coronary artery disease (Kresse et al 2009;Yen et al 2009). Interestingly, EIF2AK2, involved in influenza infection pathways (McAllister et al 2010;Pereira et al 2010), is located ;200 Kb away from the peak (2p22) showing the second highest excessive European ancestry, which suggested the possible difference between African and European resistance to influenza. PACRG, located in 6q26, is associated with Parkinson's disease.…”

Section: à16mentioning

confidence: 98%

Genome-wide detection of natural selection in African Americans pre- and post-admixture

Jin¹,

Xu²,

Wang³

et al. 2011

Genome Res.

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It is particularly meaningful to investigate natural selection in African Americans (AfA) due to the high mortality their African ancestry has experienced in history. In this study, we examined 491,526 autosomal single nucleotide polymorphisms (SNPs) genotyped in 5210 individuals and conducted a genome-wide search for selection signals in 1890 AfA. Several genomic regions showing an excess of African or European ancestry, which were considered the footprints of selection since population admixture, were detected based on a commonly used approach. However, we also developed a new strategy to detect natural selection both pre-and post-admixture by reconstructing an ancestral African population (AAF) from inferred African components of ancestry in AfA and comparing it with indigenous African populations (IAF). Interestingly, many selection-candidate genes identified by the new approach were associated with AfA-specific highrisk diseases such as prostate cancer and hypertension, suggesting an important role these disease-related genes might have played in adapting to a new environment. CD36 and HBB, whose mutations confer a degree of protection against malaria, were also located in the highly differentiated regions between AAF and IAF. Further analysis showed that the frequencies of alleles protecting against malaria in AAF were lower than those in IAF, which is consistent with the relaxed selection pressure of malaria in the New World. There is no overlap between the top candidate genes detected by the two approaches, indicating the different environmental pressures AfA experienced pre-and post-population admixture. We suggest that the new approach is reasonably powerful and can also be applied to other admixed populations such as Latinos and Uyghurs.

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Novel role for the double‐stranded RNA‐activated protein kinase PKR: modulation of macrophage infection by the protozoan parasiteLeishmania

Cited by 51 publications

References 48 publications

Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

Differential Effects of Three CanonicalToxoplasmaStrains on Gene Expression in Human Neuroepithelial Cells

Genome-wide detection of natural selection in African Americans pre- and post-admixture

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