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Susceptibility of Marmosets (Callithrix jacchus) to Monkeypox Virus: A Low Dose Prospective Model for Monkeypox and Smallpox Disease.

Mucker EM, Chapman J, Huzella LM, Huggins JW, Shamblin J, Robinson CG, Hensley LE - PLoS ONE (2015)

Bottom Line: Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course.In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset.Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans.

View Article: PubMed Central - PubMed

Affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America; Tulane University School of Medicine, New Orleans, Louisianna, United States of America.

ABSTRACT
Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course. This is a concern when developing smallpox and/or monkeypox countermeasures or trying to understand host pathogen relationships. In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset. Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans. The low dose (48 plaque forming units) required to elicit a uniformly lethal disease and the extended incubation (preclinical signs) are unique features among nonhuman primate models utilizing monkeypox virus. The uniform lethality, hemorrhagic rash, high viremia, decrease in platelets, pathology, and abbreviated acute phase are reflective of early-type hemorrhagic smallpox.

No MeSH data available.


Related in: MedlinePlus

Rash presentation of marmosets intravenously exposed to decreasing doses of monkeypox virus.Notice the rash becomes more focal in nature as the dose is decreased: 2.4 x 107 PFU, A, 9.5 x 105 PFU, B, 7.8 x 104 PFU, C, 5.0 x 103 PFU, D, 510 PFU, E, and 48 PFU.
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pone.0131742.g002: Rash presentation of marmosets intravenously exposed to decreasing doses of monkeypox virus.Notice the rash becomes more focal in nature as the dose is decreased: 2.4 x 107 PFU, A, 9.5 x 105 PFU, B, 7.8 x 104 PFU, C, 5.0 x 103 PFU, D, 510 PFU, E, and 48 PFU.

Mentions: Groups of three marmosets (a total of eighteen) were intravenously exposed to six decreasing doses of MPXV. We chose a starting target dose of 5x107 PFU as this dose is commonly used in the intravenous macaque model [12]. Animals were challenged with either 2.4x107, 9.5x105, 7.8 x104, 5.0x103, 510, or 48 PFU, as established by titration of the inoculums. All animals developed a similar disease course and died or were euthanized by day 15 post-infection (Fig 1). One animal died from causes unrelated to experimental infection, and data pertaining to this animal was excluded. The major differences between the doses were the temporal onset of disease and the phenotypic presentation of rash (Figs 2 and 3). These differences can be generally categorized into three groups: (1) animals succumbing relatively quickly, characterized by generalized hemorrhagic manifestations, (2) animals that survived longer and had more focal/discrete epidermal lesions, and (3) animals that were intermediate (between 1 and 2) for both survival and rash presentation. More specifically, animals in the highest dose group had definable clinical signs on day two, decreased activity, anterior abdominal matting of haircoat, and an unkempt appearance. By day three, a cutaneous rash (generalized anterior erythema and few petechiae), significant lymphadenopathy, and pronounced lethargy were observed in two of three animals. These clinical signs became more severe, with animals becoming somnolent before succumbing to the disease by day 9. In fact, the disease was so severe that we opted to skip a challenge dose. In contrast, lymphadenopathy and rash in the lowest dose group were not observed until at least day 9 and the earliest time point for euthanasia in this group was on day 14. The lesions in this group were much more discrete and were composed of flat, well-defined lesions that appeared dark red but never progressed through the typical stages of classic orthopoxvirus disease (Fig 2). The disease manifested in animals infected with 9.5x105 PFU and 510 PFU, resembled their higher or lower dose counterparts, respectively. Animals in the remaining two dosing groups (7.8 x104 and 5.0x103 PFU) had slightly mixed presentations, with generalized hemorrhagic manifestations and few focal lesions. The appearance of the rash and lymphadenopathy relative to the day they succumbed/euthanized tended to be more animal specific, rather than dose specific. For instance, there was variation from 0–10 days between onset of rash/lymphadenopathy and death (Fig 3).


Susceptibility of Marmosets (Callithrix jacchus) to Monkeypox Virus: A Low Dose Prospective Model for Monkeypox and Smallpox Disease.

Mucker EM, Chapman J, Huzella LM, Huggins JW, Shamblin J, Robinson CG, Hensley LE - PLoS ONE (2015)

Rash presentation of marmosets intravenously exposed to decreasing doses of monkeypox virus.Notice the rash becomes more focal in nature as the dose is decreased: 2.4 x 107 PFU, A, 9.5 x 105 PFU, B, 7.8 x 104 PFU, C, 5.0 x 103 PFU, D, 510 PFU, E, and 48 PFU.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492619&req=5

pone.0131742.g002: Rash presentation of marmosets intravenously exposed to decreasing doses of monkeypox virus.Notice the rash becomes more focal in nature as the dose is decreased: 2.4 x 107 PFU, A, 9.5 x 105 PFU, B, 7.8 x 104 PFU, C, 5.0 x 103 PFU, D, 510 PFU, E, and 48 PFU.
Mentions: Groups of three marmosets (a total of eighteen) were intravenously exposed to six decreasing doses of MPXV. We chose a starting target dose of 5x107 PFU as this dose is commonly used in the intravenous macaque model [12]. Animals were challenged with either 2.4x107, 9.5x105, 7.8 x104, 5.0x103, 510, or 48 PFU, as established by titration of the inoculums. All animals developed a similar disease course and died or were euthanized by day 15 post-infection (Fig 1). One animal died from causes unrelated to experimental infection, and data pertaining to this animal was excluded. The major differences between the doses were the temporal onset of disease and the phenotypic presentation of rash (Figs 2 and 3). These differences can be generally categorized into three groups: (1) animals succumbing relatively quickly, characterized by generalized hemorrhagic manifestations, (2) animals that survived longer and had more focal/discrete epidermal lesions, and (3) animals that were intermediate (between 1 and 2) for both survival and rash presentation. More specifically, animals in the highest dose group had definable clinical signs on day two, decreased activity, anterior abdominal matting of haircoat, and an unkempt appearance. By day three, a cutaneous rash (generalized anterior erythema and few petechiae), significant lymphadenopathy, and pronounced lethargy were observed in two of three animals. These clinical signs became more severe, with animals becoming somnolent before succumbing to the disease by day 9. In fact, the disease was so severe that we opted to skip a challenge dose. In contrast, lymphadenopathy and rash in the lowest dose group were not observed until at least day 9 and the earliest time point for euthanasia in this group was on day 14. The lesions in this group were much more discrete and were composed of flat, well-defined lesions that appeared dark red but never progressed through the typical stages of classic orthopoxvirus disease (Fig 2). The disease manifested in animals infected with 9.5x105 PFU and 510 PFU, resembled their higher or lower dose counterparts, respectively. Animals in the remaining two dosing groups (7.8 x104 and 5.0x103 PFU) had slightly mixed presentations, with generalized hemorrhagic manifestations and few focal lesions. The appearance of the rash and lymphadenopathy relative to the day they succumbed/euthanized tended to be more animal specific, rather than dose specific. For instance, there was variation from 0–10 days between onset of rash/lymphadenopathy and death (Fig 3).

Bottom Line: Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course.In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset.Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans.

View Article: PubMed Central - PubMed

Affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America; Tulane University School of Medicine, New Orleans, Louisianna, United States of America.

ABSTRACT
Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course. This is a concern when developing smallpox and/or monkeypox countermeasures or trying to understand host pathogen relationships. In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset. Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans. The low dose (48 plaque forming units) required to elicit a uniformly lethal disease and the extended incubation (preclinical signs) are unique features among nonhuman primate models utilizing monkeypox virus. The uniform lethality, hemorrhagic rash, high viremia, decrease in platelets, pathology, and abbreviated acute phase are reflective of early-type hemorrhagic smallpox.

No MeSH data available.


Related in: MedlinePlus