TWiV 355: Baby’s first virome

On episode #355 of the science show This Week in Virology, the TWiV team considers the effect of a Leishmaniavirus on the efficacy of drug treatment, and the human fecal virome and microbiome in twins during early infancy.

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A virus in a parasite in a human

Cutaneous leishmaniaThe protozoan parasite Leishmania, transmitted to humans by the bite of a sandfly, may cause disfiguring skin lesions. A virus within the parasite appears to increase the risk of treatment failure with anti-leishmania drugs.

A double-stranded RNA virus was found over 20 years ago to infect different species of Leishmania, with up to 50% of clinical isolates infected. Leishmaniavirus (LRV) causes a chronic infection with little effect on the parasite. In mouse models, infection of Leishmania with LRV is associated with increased parasite replication and disease severity. The double-stranded RNA genome of LRV appears to be sensed by the mammalian innate immune system, leading to overproduction of cytokines and a hyper-inflammatory response. Similarly, the dsRNA of Trichomonas vaginalis virus is also sensed by the innate immune system, leading to inflammatory complications.

Two independent studies have been done to assess the consequence of LRV infection in human cases of leishmaniasis. In one study, presence of LRV was determined in Leishmania braziliensis isolated from 97 patients in Peru and Bolivia. The patients were treated with pentavalent antimonials or amphotericin B, and the outcome was determined as ‘cured’ or ‘failure’. Thirty-two (33%) Leishmania isolates were found to contain LRV.   Treatment failed in 33% of the patients (18 of 54). There were fewer drug failures in the LRV negative isolates (9 of 37, 24%) than in the LRV positive isolates 9 of 17, 53%). These observations demonstrate that presence of LRV is associated with a significant increase in the risk of treatment failure.

In the second study, carried out in French Guiyana, 58% of 75 patients with Leishmania guyanensis infection had LRV in the parasite. All the patients with LRV-negative Leishmania were cured after one or two treatments with pentamidine, while 12 of 44 LRV-positive patients (27%) had persistent infections requiring treatment with other drugs. In addition, presence of LRV was associated with high levels of inflammatory cytokines within lesions.

The results of both studies show that infection of Leishmania with LRV is associated with drug treatment failure and persistent infection. Determining whether LRV is present in infected patients could therefore guide better treatment strategies. How the presence of the virus leads to such consequences is unknown. The effect might be a consequence of higher parasite numbers associated with LRV infection, which simply overcome already marginal drugs. The host inflammatory response caused by the dsRNA of LRV might also play a role. Understanding the precise mechanism might allow the development of drugs that overcome the effects of LRV. It might also be useful to develop drugs that target LRV, thereby improving the efficacy of anti-Leishmania drugs.

Viruses of protozoan parasites may exacerbate human disease

TrichomonasMany protozoan parasites (Trichomonas, Leishmania, Giardia, Plasmodium, Entamoeba, Nagleria, Eimeria, Cryptosporidium) are infected with viruses. These viruses do not infect vertebrates, but their double-stranded RNA genomes are sensed by the innate immune system, leading to inflammatory complications of protozoan infections.

Trichomonas vaginalis is a protozoan parasite that infects the genitourinary tract of ~250 million individuals each year, leading to bacterial vaginosis, increased susceptibility to human immunodeficiency virus (HIV) and human papillomavirus (HPV), and reproductive complications such as infertility, pregnancy loss, and preterm delivery. Antibiotic treatment can clear the parasite but does not prevent some of these complications.

Half of T. vaginalis clinical isolates harbor dsRNA viruses (TVV) that do not harm their parasite host. It has been suggested that these TVVs are sensed by the human host, leading to inflammation and reproductive complications. To test this hypothesis, human epithelial cell cultures from the female reproductive tract were exposed to TVV-negative or positive T. vaginalis. Virus-positive parasites induced the production of interferon and proinflammatory cytokines while virus-negative parasites did not. The production of these cytokines is dependent upon Toll-like receptor 3 (TLR3), which is present on the inner endosome membrane. This observation suggests that virions or viral RNA released from T. vaginalis are taken into the cell by endocytosis where they encounter TLR3. In support of this idea, the addition of purified TVV virions to cells lead to TLR3-dependent production of cytokines.

To provide a plausible explanation for the failure of antibiotics to prevent T. vaginalis associated complications, protozoans with or without TVV were treated with metronidazole for 24 h, and the cell supernatant was added to cell cultures. Supernatants from the virus-containing, drug treated protozoa induced cytokines in a TLR3-dependent manner. Cytokines were not induced using supernatants of T. vaginalis lacking TVV, or from cells that were not treated with antibiotics. These results suggest that antibiotic treatment of virus-infected T. vaginalis causes an inflammatory response by liberating TVV virions or viral dsRNA from the protozoan.

These intriguing results show that protozoan viruses can be sensed by human cells, leading to an inflammatory response. In the vaginal mucosa this response is a double-edged sword: it can help limit infection but may also lead to pathological damage and increased susceptibility to bacterial and viral infection. Clinical studies are needed to determine if inflammation caused by TVV is linked to T. vaginalis associated disease and complications. The outcome of this work may determine whether the use of antivirals to inhibit TVV replication, or anti-inflammatory agents, should accompany antibiotic therapy to prevent the complications associated with T. vaginalis infection.

TWiV 128: Virologists in the mist

gorillaHosts: Vincent Racaniello, Alan Dove, Dickson Despommier, and Welkin Johnson

Vincent, Alan, Dickson and Welkin review how a virus regulates the severity of mucocutaneous leishmaniasis, virophage control of antarctic algal host-virus dynamics, and human metapneumovirus infection in gorillas.

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Welkin – Walter Reed Collection, University of Virginia
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Vincent – Potential bacteriophage applications (Microbe)

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TWiP 14: Leishmania

Hosts: Vincent Racaniello and Dickson Despommier

On episode 14 of the podcast This Week in Parasitism, Vincent and Dickson consider the life cycle and pathogenesis of the protozoan parasite Leishmania.

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Download TWiP #14 (61 MB .mp3, 85 minutes)

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