We recently published an article in the in the journal Foreign Policy about the surprising number of these diseases affecting the extreme poor who live in wealthy countries such as the United States. Feel free to explore the National School of Tropical Medicine website and ask questions about neglected tropical diseases affecting poor people both globally and here in Texas and even Houston.
Your email address will not be published. Notify me of follow-up comments by email. Notify me of new posts by email. Skip to content. Peter Hotez The high degree of lethality of Guanarito has prompted the U. You May Also Like. Online event provides perspective students insight into admissions, College October 17, October 7, Intriguingly, Amapari and Tacaribe viruses can infect and replicate in human cells, but they do so independently of human TfR1, although they efficiently use the TfR1 of their respective hosts 5 , However, a point mutation was enough to convert human TfR1 into an efficient receptor for Tacaribe virus, and four mutations within nucleotides found in the host species Neacomys spinosus TfR1 sequence converted human TfR1 into an efficient receptor for Amapari virus 5.
Likewise, human TfR1 variants with only modest changes allow efficient infection by tentative clade D viruses, implying that a small number of mutations in the GP may be sufficient for these viruses to gain use of human TfR1.
These data show that TfR1 has an important role in the replication of nonpathogenic NW arenaviruses and suggest that subtle changes in their GPs might adapt them to use human TfR1. Moreover, lack of host species specificity among the clade D viruses may promote cross-species transmission and recombination, which can in turn increase the likelihood of producing viruses that use human TfR1. The North American arenaviruses may infect humans more frequently than previously understood given that only modest changes in receptor recognition are needed to change species tropism This highlights the potential of these viruses to emerge as human pathogens.
Thus, the ability of an arenavirus to use human TfR1 is predictive of its ability to cause hemorrhagic fevers in humans The close relationship between human TfR1 use and severe human disease suggests that TfR1 regulation plays a pivotal role in disease severity.
TfR1 has several properties favorable to arenavirus replication and the development of hemorrhagic fevers: It is rapidly endocytosed into acidic compartments, is expressed on endothelial cells, and is upregulated on rapidly dividing cells including activated lymphocytes 5.
The early response to viral infection thus could drive TfR1 expression on activated target cells, which in turn would accelerate viral replication; this feedback mechanism could distinguish clade B hemorrhagic fever arenaviruses from the nonpathogenic variants that have the ability to infect cells using other receptors that may not be upregulated in response to infection Because TfR1 expression is highly regulated by host iron levels, it has been suggested that treatment of infected individuals with iron might ameliorate disease 42 , 43 , NW arenaviruses also enter cells via TfR1-independent means 48 , 51 and likely use receptors other than TfR1 to infect sentinel cells of the immune system, their probable initial in vivo targets see below.
This must also be the case for the nonpathogenic clade B viruses Tacaribe virus, Amapari virus, and Flexal virus, which can infect human cells or humans independently of TfR1 28 , Although human TfR1 is the primary cell entry receptor for these viruses, NW arenaviruses can infect murine cell lines, macrophage primary cultures from rat and C.
Some of these other receptors, as well as TfR1, may serve to increase binding of NW arenaviruses to the cell surface, thereby increasing the local concentration of virions and the efficacy of infection. Whereas the GP1 subunit primarily determines host and likely tissue tropism by binding to the cell surface receptors, the GP2 subunit mediates membrane fusion, along with the SSP subunit, after virus particles are internalized into acidified endosomes.
Subsequent to GP interaction with receptors on the cell surface, trafficking to a pH 5 late endosomal compartment is required for virus-cell membrane fusion and entry of the capsid into cells Figure 2b 59 — Internalization may occur through clathrin-mediated endocytosis, although this has only been shown in immortalized epithelial cells and fibroblasts Although it has been suggested that NW arenaviruses traffic through an early endocytic compartment to reach the late endosome, we as well as others have suggested that the virus bypasses the early compartment, at least in certain cell types 62 — 64 ; one possibility is that NW arenavirus entry through intracellular compartments differs depending on the cell type.
Both the TfR1-dependent pathway and the TfR1-independent pathway still require entry through a low-pH compartment 56 , Arenavirus replication is confined to the cytoplasm. Subsequent to entry into the cytoplasm, the L protein begins transcription and replication of the viral antigenome.
NP and L are the first to be transcribed and translated; translation of GPC and Z requires synthesis of the viral antigenome and subsequent transcription. Arenavirus genome and virion structure. Both RNAs are ambisense. As discussed above, the L polymerase is likely error-prone, generating a relatively high mutation frequency with the potential to produce viruses with novel host tropism.
NP and Z are also believed to be important for mediating viral RNA synthesis and translation 71 , The viruses then bud from the plasma membrane, which has already incorporated the viral GP1 and GP2 glycoprotein subunits in association with the SSP glycoprotein subunit Figure 2b The name arenaviruses derives from the sandy arena in Greek appearance of the capsid interior in electron micrographs 66 Figure 3b.
The particles that lend this sandy appearance are packaged host ribosomes; the role, if any, of these ribosomes in virus replication is not known. Like many viral hemorrhagic fevers, the early clinical signs of NW arenavirus infections include flu-like symptoms such as fever, malaise, headache, conjunctivitis, nausea, vomiting, and diarrhea, so NW arenavirus disease is difficult to diagnose in the absence of a known outbreak Patient survival is characterized by a robust neutralizing antibody response Outright hemorrhaging from multiple mucosal surfaces is rare in NW arenavirus infection.
More common are petechiae in oral mucosa and the chest, arms, and axillary region, as well as gingival bleeding. Untreated, severe disease is often accompanied by ataxia, mental confusion, increased irritability, and tremors and can progress to seizures and coma.
The causes of these symptoms are not well understood. Endothelial cell and platelet dysfunction caused by direct viral infection have been documented in vitro, but whether this occurs in vivo is not known 77 — Indeed, there is little or no evidence of overt endothelial damage in infected humans.
While NW arenaviruses infect many different cell types in vitro and ex vivo, the exact targets during human infection are not clear. This lack of in vitro specificity may be linked to the high levels of TfR1 expression on cells in culture; TfR1 is highly upregulated in actively dividing cells because it is the major means by which cells take up iron In contrast, most cells in vivo express low or no TfR1 unless activated or dividing.
This includes lymphocytes and sentinel cells of the immune system as well as mucosal epithelia. There is evidence from both human and animal studies that macrophages and dendritic cells are major primary targets of NW arenavirus infection after airborne infection, likely those cells resident in the lung 81 — Interestingly, this is reminiscent of another virus, the milkborne mouse mammary tumor virus, which also uses TfR1 for entry, and whose initial in vivo targets are dendritic cells located in the intestinal mucosa 87 , Infection of macrophages and dendritic cells may lead to aberrant cytokine production and bystander effects on endothelial and other cells affected by NW arenavirus infection There are a number of animal models that recapitulate some but not all of the pathologies associated with NW arenavirus infection in humans.
In fact, the amino acid changes in the Candid 1 GP appear to have made this strain more dependent on human TfR1 than the wild-type virus from which it was derived; however, these changes were not sufficient to completely attenuate the virus in a guinea pig or mouse model 93 — Whether the amino acid changes in the L gene encoding the viral polymerase or alterations in RNA secondary structure due to nucleotide changes are also needed for full attenuation is not clear 52 , When the Candid 1 L gene was substituted for the pathogenic Romero L gene it did not attenuate viral replication kinetics in vitro, but whether this substitution would affect in vivo infection is not known As a result, knockout mice lacking this receptor sustained a more long-term infection with Candid 1 than did wild-type mice, due at least in part to diminished CD8 T cell responses.
However, both wild-type and TLR2 knockout mice mounted strong humoral immune antibody responses that rapidly cleared virus. Interestingly, direct intracranial inoculation of Candid 1 into wild-type mice generated a TLR2-dependent cytokine response that did not diminish infection levels, suggesting that the virus could replicate in the brain unimpeded by the host innate immune response In this model, both astrocytes and microglia were infected.
Whether outright infection of the brain occurs in human infection, leading to the neurological syndromes, is not known.
Pathogenesis in humans, including endothelial dysfunction, may rely on high cytokine levels induced by the virus, and mice lacking interferon receptors would therefore lack this aspect of the infection.
It is not known what receptor NW arenaviruses use in mice, although, as mentioned above, the L-type voltage-gated calcium channels can function as entry receptors in mouse cells Because NW arenaviruses use alternate receptors in mice, the in vivo cell type tropism may differ from that in humans; this could also contribute to the altered pathogenic phenotype.
While the currently studied mouse models with immunological dysfunction may be useful to test antiviral therapeutics, because of the differences in disease outcome and the lack of a full immune response, they most likely are not useful for understanding the effects of in vivo infection.
Other animal models, including hamsters, succumb to infection with NW arenaviruses that do not cause disease in humans, including the lineage A Pirital virus, an arenavirus isolated in western Venezuela during epidemiologic studies of Venezuelan hemorrhagic fever Similarly, ribavirin was also shown to be effective in monkeys , Although primates are clearly useful for testing therapeutics and vaccine strategies, the difficulty of working with ABSL-4 agents in large animals precludes their usefulness as an experimental model to study disease progression.
A number of viral proteins have been implicated in suppressing the host immune response to NW arenavirus infection. Both the NP and Z proteins of NW arenaviruses have been shown to block type I interferon production, both in tissue culture and in animal models , However, given the high levels of interferon and cytokine induced by virus in cultured cells, in animal models, and in humans, as discussed above, it is not entirely clear whether the virus uses these antihost mechanisms in in vivo infection.
Although the Candid 1 vaccine has been highly effective in reducing the incidence of Argentine hemorrhagic fever, there are few treatments available for unvaccinated individuals or for those infected with the other hemorrhagic fever viruses found in South America 4 — 6.
However, it has never been formally tested whether convalescent serum would work to treat hemorrhagic fevers caused by the other NW arenaviruses, and as of yet, no similar monoclonals to the other viruses have been developed. Moreover, there is the potential for new NW arenavirus zoonoses, as discussed above. Whether it will be possible to develop pan-NW arenavirus antibodies to be used in treatment is not known.
Thus, new antiarenaviral therapies are still needed. Several promising leads have been developed over recent years, resulting from both small interfering RNA siRNA and drug high-throughput screens. Several groups have focused on inhibiting viral entry, and inhibitors to this step in infection have been developed, although only a few have been tested in mouse models as well as tissue culture cells 58 , — Some of these inhibitors, such as gabapentin, which targets the voltage-gated calcium channel implicated as an entry receptor, are highly specific for NW arenaviruses, whereas others likely target a more general entry step because they are effective on multiple virus families 58 , Ribavirin is a nucleoside analog that inhibits the viral L polymerase of all arenaviruses, with significant side effects in some individuals 17 , Several novel inhibitors of the polymerase, including favipiravir and A3, a pyrimidine biosynthesis inhibitor, have shown promise in guinea pig and tissue culture models, respectively , A compound that inhibits virus budding has also been identified by in silico screening Like some of the inhibitors of entry, these polymerase and exit molecules are likely to function as pan-virus inhibitors.
Although much has been learned in recent years about the biology of the NW pathogenic arenaviruses, they still remain of serious concern to human health because of the lack of effective vaccines and the relative dearth of antiviral pharmaceuticals.
Additionally, there are a large number of these viruses residing in rodent hosts endemic to different regions of the Americas, with the potential to zoonose into humans. The development of tissue culture cell and animal models has provided much information about the biology of these viruses, but there is still much to be learned about how they cause disease in humans.
A better understanding of NW arenavirus-host interactions and pathogenesis is needed for the development of therapeutics that can be used to treat infection. Are novel mammarenaviruses generated only by error-prone viral polymerases, or can they also be generated by recombination after coinfection of a single host with two viruses?
What receptors allow the viruses to enter cells of nonhost species, and are additional subcellular or endosomal proteins involved in entry? How can mouse models be generated that faithfully recapitulate human disease?
Would expression of human TfR1 in a mouse render it susceptible to NW arenavirus-induced disease? Is pathogenesis directly caused by viral infection, or does the host immune response also play a role?
We thank the members of our lab for helpful discussions and Christian Cuevas for some of the figures. The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.
National Center for Biotechnology Information , U. Annu Rev Virol. Author manuscript; available in PMC Sep 8. Author information Copyright and License information Disclaimer. Email: ude. Copyright notice. The publisher's final edited version of this article is available at Annu Rev Virol. See other articles in PMC that cite the published article.
Abstract Hemorrhagic fevers caused by viruses were identified in the late s in South America. Keywords: arenavirus, transferrin receptor, animal models. Open in a separate window.
Figure 1. Figure 2. Figure 3. Identification, characterization, and in vitro culture of highly divergent arenaviruses from boa constrictors and annulated tree boas: candidate etiological agents for snake inclusion body disease. Past, present, and future of arenavirus taxonomy. Virol —74 [ PubMed ] [ Google Scholar ]. Presence of viral particles in the salivary gland of Calomys musculinus infected with Junin virus by a natural route.
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A XXI century update. Microbes Infect. Although not the cause of the outbreak, LCMV was found to be a cause of nonbacterial meningitis. Since then, new arenaviruses have been discovered regularly. While rodent hosts are chronically infected with an arenavirus, they do not appear to become ill. Most infections spread among adult rodents through scratches and bites, although for certain arenaviruses, the virus passes from mother to offspring during pregnancy.
Arenaviruses are shed into the environment in the urine, saliva, or droppings of infected rodent hosts. People become infected by breathing in the virus after rodent urine, droppings, or nesting materials are stirred up, such as during cleaning. People can also get infected by touching their face after touching the virus, through the bites or scratches of infected rodents, and by eating contaminated food.
In some instances, arenaviruses can spread to people when consuming infected rodents as a food source. Person-to-person transmission can occur with certain arenaviruses, such as Chapare, Lassa, Machupo, and Lujo viruses. This type of transmission usually occurs when there is direct contact with the blood or other body fluids of infected individuals. Contact with contaminated objects, such as medical equipment, is also associated with spreading these viruses.
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