The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset

With up to 500,000 infections annually, Lassa virus (LASV), the cause of Lassa fever, is one of the most prevalent etiological agents of viral hemorrhagic fever (VHF) in humans. LASV is endemic in several West African countries with sporadic cases and prolonged outbreaks observed most commonly in Sierra Leone, Liberia, Guinea and Nigeria. Additionally several cases of Lassa fever have been imported into North America, Europe and Asia making LASV a global threat to public health. Despite this, currently no approved therapeutic or vaccine exists to treat or prevent LASV infections. Here, using a passaged strain of LASV that is uniformly lethal in Hartley guinea pigs, we demonstrate that favipiravir, a broad-spectrum antiviral agent and leading treatment option for influenza, has potent activity against LASV infection. In this model, once daily treatment with favipiravir significantly reduced viral titers in tissue samples and reduced mortality rates when compared with animals receiving vehicle-only or ribavirin, the current standard of care for Lassa fever. Favipiravir remained highly effective against lethal LASV infection when treatments were initiated nine days post-infection, a time when animals were demonstrating advanced signs of disease. These results support the further preclinical evaluation of favipiravir for Lassa fever and other VHFs

Characterization of a Novel STAT 2 Knock Out Hamster Model of Crimean Congo Hemorrhagic Fever Virus Pathogenesis

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen causing a febrile illness in humans, which can progress to hemorrhagic manifestations, multi-organ failure, and death. Current mouse models of CCHFV infection reliably succumb to virus challenge but vary in their ability to reflect signs of disease similar to humans. In this study, we established a signal transducer and activator of transcription 2 (STAT2) knockout hamster model to expand the repertoire of animal models of CCHFV pathogenesis that can be used for therapeutic development. These hamsters demonstrated a systemic and lethal disease in response to infection. Hallmarks of human disease were observed including petechial rash, blood coagulation dysfunction, and various biochemistry and blood cell count abnormalities. Furthermore, we also demonstrated the utility of this model for anti-CCHFV therapeutic evaluation. The STAT2 knock-out hamster model of CCHFV infection may provide some further insights into clinical disease, viral pathogenesis, and pave the way for testing of potential drug and vaccine candidates

SARS-Like coronavirus WIV1-CoV does not replicate in Egyptian fruit bats (Rousettus aegyptiacus)

Severe acute respiratory syndrome (SARS)-like WIV1-coronavirus (CoV) was first isolated from Rhinolophus sinicus bats and can use the human angiotensin converting enzyme 2 (ACE2) receptor. In the current study, we investigate the ability of WIV1-CoV to infect Rousettus aegyptiacus bats. No clinical signs were observed throughout the experiment. Furthermore, only four oropharyngeal swabs and two respiratory tissues, isolated on day 3 post inoculation, were found positive for viral RNA. Two out of twelve bats showed a modest increase in coronavirus specific antibodies post challenge. In conclusion, WIV1-CoV was unable to cause a robust infection in Rousettus aegyptiacus bats

Use of Favipiravir to Treat Lassa Virus Infection in Macaques

Lassa virus, the cause of Lassa fever in humans, is endemic to West Africa. Treatment of Lassa fever is primarily supportive, although ribavirin has shown limited efficacy if administered early during infection. We tested favipiravir in Lassa virus–viremic macaques and found that 300 mg/kg daily for 2 weeks successfully treated infection

Hydroxychloroquine prophylaxis and treatment is ineffective in macaque and hamster SARS-CoV-2 disease models

open access articleWe remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human COVID-19 clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies to help guide decisions. Here we assessed the prophylactic/ therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in 2 animal disease models. The standard human malaria HCQ prophylaxis (6.5 mg/kg given weekly) and treatment (6.5 mg/kg given daily) did not significantly benefit clinical outcome, nor did it reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. Similarly, when used for prophylaxis or treatment, neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Results from these 2 preclinical animal models may prove helpful in guiding clinical use of HCQ for prophylaxis/treatment of COVID-19

Histopathologic Characterization of Experimental Peracute SARS-CoV-2 Infection in the Syrian Hamster

Coronavirus Infectious Disease 2019 (COVID-19) initiated a global pandemic that thus far has resulted in the death of over 6.5 million people internationally. Understanding the viral tropism during the initial, subclinical phase of infection is critical to develop targeted vaccines and therapeutics. With the continued emergence of variants of concern, particularly those that appear to have a tropism for the upper respiratory tract, understanding the complete pathogenesis is critical to develop more effective interventions. Thus far, the Syrian hamster has served as the most consistent small animal model of SARS-CoV-2 infection for mild to moderate respiratory disease. Herein, we utilize histopathology and immunohistochemistry to characterize the peracute phase of disease initiating at 6-h-post-inoculation in the intranasal inoculation route Syrian hamster model. Inflammation and viral replication initiates in the respiratory epithelium of nasal turbinates as early as 12-h-post-inoculation and moves caudally through the nasal cavity by 36-h-post inoculation. Lower respiratory involvement can be detected as early as 12-h-post inoculation in the intranasal inoculated hamster model. These data highlight the importance of rostral nasal cavity sampling at early timepoints for detection of SARS-CoV-2 in the Syrian hamster model

Distribution of POWV RNA in the CNS of i.c. inoculated determined by <i>in situ</i> hybridization.

<p>(<b>A</b>) POWV (+)RNA (stained brown) in the brain and spinal cord of i.c. inoculate <i>P</i>. <i>leucopus</i> mice. (<b>i</b>) Negative control showing no POWV (+)RNA. <b>(ii)</b> Diffuse detection of (+)RNA in the olfactory bulb (magnification x20). <b>(iii)</b> Close up image of the olfactory bulb (magnification x200). <b>(iv)</b> Multifocal detection of POWV (+)RNA in the paraventricular region of the brain. (<b>v</b>) Multifocal detection of POWV (+) RNA in the cerebellum. (<b>vi</b>) Multifocal detection of POWV (+)RNA in the spinal cord. (<b>B</b>) Detection of POWV negative RNA strand ((-)RNA) in the brains of <i>Peromyscus leucopus</i>, BALB/c and C57BL/6 mouse brains after ic inoculation. We used probes targeting the (-)RNA of POWV, which is only present during virus replication. (<b>i</b>) No viral RNA was detected in the mock-inoculated <i>P</i>. <i>leucopus</i> control. (<b>ii</b>) POWV (-)RNA was strongly and diffusely detected in the olfactory lobe of i.c. inoculated <i>P</i>. <i>leucopus</i>. (iii) Detection of diffuse POWV (-)RNA in the brain of an i.c. inoculated C57BL/6 mouse. (iv) Detection of diffuse POWV (-)RNA in the brain of an i.c. inoculated BALB/c mouse.</p

Analysis of i.p. inoculation of POWV in BALB/c and C57BL/6 mice.

<p><b>(A)</b> Survival curve for i.p. inoculated BALB/c, C57BL/6 and P. leucopus mice. <b>(B)</b> Changes in weights of BALB/c mice after i.p. inoculation of POWV. <b>(C)</b> Changes in weights of BALB/c mice after ip inoculation of POWV. <b>(D)</b> POWV (+)RNA copy numbers in brains of i.p.-inoculated BALB/c and C57BL/6 mice. The red dot for BALB/c mice denotes RNA copy numbers from the mouse which succumbed first. The red square for C57BL/6 mice denotes the mouse that succumbed at 8 dpi, the black squares represent the mice that succumbed at 11 dpi and the survivors are denoted by the purple squares. ns: not significant (t-test).</p

Detection of POWV (+)RNA in the brain and spinal cord by <i>in situ</i> hybridization after i.c. inoculation.

<p>Diffuse positivity was observed in the brains of both BALB/c and C57BL/6 mice at 4 or 5 dpi. Positivity in the spinal cord was diffuse in BALB/c mice, but multi-focal in C57BL/6 mice. No viral RNA could be visualized in the brain and spinal cord of <i>P</i>. <i>leucopus</i> mice at 28 dpi.</p

Severity of Disease in Humanized Mice Infected With Ebola Virus or Reston Virus Is Associated With Magnitude of Early Viral Replication in Liver.

Both Ebola virus (EBOV) and Reston virus (RESTV) cause disease in nonhuman primates, yet only EBOV causes disease in humans. To investigate differences in viral pathogenicity, humanized mice (hu-NSG-SGM3) were inoculated with EBOV or RESTV. Consistent with differences in disease in human infection, pronounced weight loss and markers of hepatic damage and disease were observed exclusively in EBOV-infected mice. These abnormalities were associated with significantly higher EBOV replication in the liver but not in the spleen, suggesting that in this model, efficiency of viral replication in select tissues early in infection may contribute to differences in viral pathogenicity. J Infect Dis 2018 Jan; 217(1):58-63