Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

AbstractMiddle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.

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Use of a new mouse model of Acinetobacter baumannii pneumonia to evaluate the postantibiotic effect of imipenem.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.2.345 ◽

1997 ◽

Vol 41 (2) ◽

pp. 345-351 ◽

Cited By ~ 72

Author(s):

M L Joly-Guillou ◽

M Wolff ◽

J J Pocidalo ◽

F Walker ◽

C Carbon

Keyword(s):

Mouse Model ◽

Acinetobacter Baumannii ◽

Lung Pathology ◽

Postantibiotic Effect ◽

Experimental Mouse ◽

Multiresistant Strains ◽

Human Infections ◽

Dosing Intervals

Acinetobacter baumannii is responsible for severe nosocomial pneumonia. To evaluate new therapeutic regimens for infections due to multiresistant strains and to study the pharmacodynamic properties of various antibiotics, we developed an experimental mouse model of acute A. baumannii pneumonia. C3H/HeN mice rendered transiently neutropenic were infected intratracheally with 5 x 10(6) CFU of A. baumannii. The mean log10 CFU/g of lung homogenate (+/- the standard deviation) were 9 +/- 0.9, 9.4 +/- 0.8, 8.6 +/- 1.2, and 7.7 +/- 1.4 on days 1, 2, 3, and 4 postinoculation. The lung pathology was characterized by pneumonitis with edema and a patchy distribution of hemorrhages in the peribronchovascular spaces of both lungs. Abscesses formed on days 3 and 4. Four days after inoculation, subacute pneumonitis characterized by alveolar macrophage proliferation and areas of fibrosis was observed. The cumulative mortality on day 4 was 85%. This new model was used to study the effects of 1, 2, or 3 50-mg/kg doses of imipenem. Imipenem concentrations in lungs were above the MIC for 2 h after the last dose. The in vivo postantibiotic effect (PAE) was determined during the 9-h period following the last dose; it decreased in duration with the number of doses: 9.6, 6.4, and 4 h after 1, 2, and 3 50-mg/kg doses, respectively. In contrast, no in vitro PAE was observed. This model offers a reproducible acute course of A. baumannii pneumonia. The presence of a prolonged in vivo PAE supports the currently recommended dosing intervals of imipenem for the treatment of human infections due to A. baumannii, i.e., 15 mg/kg three times a day.

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An Orally Available Cathepsin L Inhibitor Protects Lungs Against SARS-CoV-2-Induced Diffuse Alveolar Damage in African Green Monkeys

10.1101/2021.07.20.453127 ◽

2021 ◽

Author(s):

Felix W Frueh ◽

Daniel C Maneval ◽

Rudolph P Bohm ◽

Jason P Dufour ◽

Robert V Blair ◽

...

Keyword(s):

Diffuse Alveolar Damage ◽

Cathepsin L ◽

Proteolytic Processing ◽

Lung Pathology ◽

Therapeutic Setting ◽

Pulmonary Pathology ◽

Agm Model ◽

Severe Lung

The COVID-19 pandemic resulted from global infection by the SARS-CoV-2 coronavirus and rapidly emerged as an urgent health issue requiring effective treatments. To initiate infection, the Spike protein of SARS-CoV-2 requires proteolytic processing mediated by host proteases. Among the host proteases proposed to carry out this activation is the cysteine protease cathepsin L. Inhibiting cathepsin L has been proposed as a therapeutic strategy for treating COVID-19. SLV213 (K777) is an orally administered small molecule protease inhibitor that exhibits in vitro activity against a range of viruses, including SARS-CoV-2. To confirm efficacy in vivo, K777 was evaluated in an African green monkey (AGM) model of COVID-19. A pilot experiment was designed to test K777 in a prophylactic setting, animals were pre-treated with 100mg/kg K777 (N=4) or vehicle (N=2) before inoculation with SARS-CoV-2. Initial data demonstrated that K777 treatment reduced pulmonary pathology compared to vehicle-treated animals. A second study was designed to test activity in a therapeutic setting, with K777 treatment (33 mg/kg or 100 mg/kg) initiated 8 hours after exposure to the virus. In both experiments, animals received K777 daily via oral gavage for 7 days. Vehicle-treated animals exhibited higher lung weights, pleuritis, and diffuse alveolar damage. In contrast, lung pathology was reduced in K777-treated monkeys, and histopathological analyses confirmed the lack of diffuse alveolar damage. Antiviral effects were further demonstrated by quantitative reductions in viral load of samples collected from upper and lower airways. These preclinical data support the potential for early SLV213 treatment in COVID-19 patients to prevent severe lung pathology and disease progression.

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Anti-viral properties of interferon beta treatment in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458502ms794oa ◽

2002 ◽

Vol 8 (3) ◽

pp. 237-242 ◽

Cited By ~ 29

Author(s):

J Hong ◽

M V Tejada-Simon ◽

V M Rivera ◽

Y CQ Zang ◽

J Z Zhang

Keyword(s):

Multiple Sclerosis ◽

Treatment Efficacy ◽

Interferon Beta ◽

Viral Infections ◽

Human Herpesvirus ◽

Virion Protein ◽

Cell Free Dna ◽

Free Dna

Viral infections are potentially associated with the etiology and pathogenesis of multiple sclerosis (MS). It has been speculated that the treatment efficacy of interferon beta (IFN beta) in MS may relate to its anti-viral properties. The study was undertaken to evaluate the in vivo anti-viral effects of IFN beta-1a in patients with MS. Human herpesvirus-6 (HHV-6) was studied as an example for being a latent neurotropic virus. IFN beta used at concentrations of approximately 0.5 mg/ml was shown to significantly reduce in vitro HHV-6 replication in a susceptible T-cell line. Sera derived from 23 MS patients treated with IFN beta-1a were examined for serum cell-free DNA of HHV-6 as an indicator for viral replication and the reactivity of IgM antibodies to a recombinant HHV-6 virion protein containing a known immunoreactive region. The results were compared with those of control sera obtained from untreated MS (n=29) and healthy individuals (n=21). The findings indicated that IFN beta treatment significantly reduced HHV-6 replication as evident by decreased cell-free DNA in treated MS specimens. The results correlated with decreased IgM reactivity to the HHV-6 antigen in treated MS patients compared to untreated controls, suggesting reduced exposure to HHV-6. The findings were confirmed in paired sera obtained from seven MS patients before and after the treatment. The study provides new evidence indicating that IFN beta has potent in vivo anti-viral effects that may contribute to the treatment efficacy in MS.

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Sickle Cell Anemia and Babesia Infection

Pathogens ◽

10.3390/pathogens10111435 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1435

Author(s):

Divya Beri ◽

Manpreet Singh ◽

Marilis Rodriguez ◽

Karina Yazdanbakhsh ◽

Cheryl Ann Lobo

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Current Knowledge ◽

Globin Gene ◽

Environmental Niche ◽

Parasite Resistance ◽

The Usa ◽

Human Infections

Babesia is an intraerythrocytic, obligate Apicomplexan parasite that has, in the last century, been implicated in human infections via zoonosis and is now widespread, especially in parts of the USA and Europe. It is naturally transmitted by the bite of a tick, but transfused blood from infected donors has also proven to be a major source of transmission. When infected, most humans are clinically asymptomatic, but the parasite can prove to be lethal when it infects immunocompromised individuals. Hemolysis and anemia are two common symptoms that accompany many infectious diseases, and this is particularly true of parasitic diseases that target red cells. Clinically, this becomes an acute problem for subjects who are prone to hemolysis and depend on frequent transfusions, like patients with sickle cell anemia or thalassemia. Little is known about Babesia’s pathogenesis in these hemoglobinopathies, and most parallels are drawn from its evolutionarily related Plasmodium parasite which shares the same environmental niche, the RBCs, in the human host. In vitro as well as in vivo Babesia-infected mouse sickle cell disease (SCD) models support the inhibition of intra-erythrocytic parasite proliferation, but mechanisms driving the protection of such hemoglobinopathies against infection are not fully studied. This review provides an overview of our current knowledge of Babesia infection and hemoglobinopathies, focusing on possible mechanisms behind this parasite resistance and the clinical repercussions faced by Babesia-infected human hosts harboring mutations in their globin gene.

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Exacerbation of Influenza A Virus Disease Severity by Respiratory Syncytial Virus Co-Infection in a Mouse Model

Viruses ◽

10.3390/v13081630 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1630 ◽

Cited By ~ 1

Author(s):

Junu A. George ◽

Shaikha H. AlShamsi ◽

Maryam H. Alhammadi ◽

Ahmed R. Alsuwaidi

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

Influenza A Virus ◽

Influenza A ◽

Immune Cell ◽

Virus Disease ◽

Viral Loads ◽

Syncytial Virus

Influenza A virus (IAV) and respiratory syncytial virus (RSV) are leading causes of childhood infections. RSV and influenza are competitive in vitro. In this study, the in vivo effects of RSV and IAV co-infection were investigated. Mice were intranasally inoculated with RSV, with IAV, or with both viruses (RSV+IAV and IAV+RSV) administered sequentially, 24 h apart. On days 3 and 7 post-infection, lung tissues were processed for viral loads and immune cell populations. Lung functions were also evaluated. Mortality was observed only in the IAV+RSV group (50% of mice did not survive beyond 7 days). On day 3, the viral loads in single-infected and co-infected mice were not significantly different. However, on day 7, the IAV titer was much higher in the IAV+RSV group, and the RSV viral load was reduced. CD4 T cells were reduced in all groups on day 7 except in single-infected mice. CD8 T cells were higher in all experimental groups except the RSV-alone group. Increased airway resistance and reduced thoracic compliance were demonstrated in both co-infected groups. This model indicates that, among all the infection types we studied, infection with IAV followed by RSV is associated with the highest IAV viral loads and the most morbidity and mortality.

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Gag-Specific Cellular Immunity DeterminesIn VitroViral Inhibition andIn VivoVirologic Control following Simian Immunodeficiency Virus Challenges of Vaccinated Rhesus Monkeys

Journal of Virology ◽

10.1128/jvi.00996-12 ◽

2012 ◽

Vol 86 (18) ◽

pp. 9583-9589 ◽

Cited By ~ 30

Author(s):

Kathryn E. Stephenson ◽

Hualin Li ◽

Bruce D. Walker ◽

Nelson L. Michael ◽

Dan H. Barouch

Keyword(s):

Simian Immunodeficiency Virus ◽

Rhesus Monkeys ◽

Viral Inhibition ◽

Viral Loads ◽

Immunodeficiency Virus ◽

Virologic Control ◽

Cellular Immune ◽

Hiv 1

A comprehensive vaccine for human immunodeficiency virus type 1 (HIV-1) would block HIV-1 acquisition as well as durably control viral replication in breakthrough infections. Recent studies have demonstrated that Env is required for a vaccine to protect against acquisition of simian immunodeficiency virus (SIV) in vaccinated rhesus monkeys, but the antigen requirements for virologic control remain unclear. Here, we investigate whether CD8+T lymphocytes from vaccinated rhesus monkeys mediate viral inhibitionin vitroand whether these responses predict virologic control following SIV challenge. We observed that CD8+lymphocytes from 23 vaccinated rhesus monkeys inhibited replication of SIVin vitro. Moreover, the magnitude of inhibition prior to challenge was inversely correlated with set point SIV plasma viral loads after challenge. In addition, CD8 cell-mediated viral inhibition in vaccinated rhesus monkeys correlated significantly with Gag-specific, but not Pol- or Env-specific, CD4+and CD8+T lymphocyte responses. These findings demonstrate thatin vitroviral inhibition following vaccination largely reflects Gag-specific cellular immune responses and correlates within vivovirologic control following infection. These data suggest the importance of including Gag in an HIV-1 vaccine in which virologic control is desired.

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Anisakiosis (Anisakidosis)

10.1093/med/9780198570028.003.0070 ◽

2011 ◽

Cited By ~ 4

Author(s):

Woon-Mok Sohn ◽

Jong-Yil Chai

Keyword(s):

Careful Examination ◽

Intermediate Hosts ◽

Fish Fillet ◽

Life Threatening ◽

Infection Source ◽

Accidental Host ◽

Human Infections ◽

Anisakid Larvae

The term ‘anisakiosis (anisakidosis)’ or ‘anisakiasis’ collectively defines human infections caused by larval anisakids belonging to the nematode family Anisakidae or Raphidascarididae. Anisakis simplex, Anisakis physeteris, and Pseudoteranova decipiens are the three major species causing human anisakiosis. Various kinds of marine fish and cephalopods serve as the second intermediate hosts and the infection source. Ingestion of viable anisakid larvae in the fillet or viscera of these hosts is the primary cause of infection. The parasite does not develop further in humans as they are an accidental host. Clinical anisakiosis develops after the penetration of anisakid larvae into the mucosal wall of the alimentary tract, most frequently the stomach and the small intestine. The affected sites undergo erosion, ulceration, swelling, inflammation, and granuloma formation around the worm. The patients may suffer from acute abdominal pain, indigestion, nausea, vomiting, and in some instances, allergic hypersensitive reactions. Symptoms in gastric anisakiosis often resemble those seen in peptic ulcer or gastric cancer, and symptoms in intestinal anisakiosis resemble those of appendicitis or peritonitis. Treatments include removal of larval worms using a gastroendoscopic clipper or surgical resection of the mucosal tissue surrounding the worm. No confirmed effective anthelmintic drug has been introduced, though albendazole and ivermectin have been tried in vivo and in vitro. Prevention of human anisakiosis can be achieved by careful examination of fish fillet followed by removal of the worms in the restaurant or household kitchen. Immediate freezing of fish and cephalopods just after catching them on fishing boats was reported helpful for prevention of anisakiosis. It is noteworthy that anisakiosis is often associated with strong allergic and hypersensitivity reactions, with symptoms ranging from isolated angioedema to urticaria and life threatening anaphylactic shock.

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Genetically and Antigenically Divergent Influenza A(H9N2) Viruses Exhibit Differential Replication and Transmission Phenotypes in Mammalian Models

Journal of Virology ◽

10.1128/jvi.00451-20 ◽

2020 ◽

Vol 94 (17) ◽

Author(s):

Jessica A. Belser ◽

Xiangjie Sun ◽

Nicole Brock ◽

Claudia Pappas ◽

Joanna A. Pulit-Penaloza ◽

...

Keyword(s):

Influenza A ◽

Human Infection ◽

Influenza Viruses ◽

Human Populations ◽

Human Respiratory Tract ◽

Live Bird Markets ◽

Human Infections ◽

Live Bird

ABSTRACT Low-pathogenicity avian influenza A(H9N2) viruses, enzootic in poultry populations in Asia, are associated with fewer confirmed human infections but higher rates of seropositivity compared to A(H5) or A(H7) subtype viruses. Cocirculation of A(H5) and A(H7) viruses leads to the generation of reassortant viruses bearing A(H9N2) internal genes with markers of mammalian adaptation, warranting continued surveillance in both avian and human populations. Here, we describe active surveillance efforts in live poultry markets in Vietnam in 2018 and compare representative viruses to G1 and Y280 lineage viruses that have infected humans. Receptor binding properties, pH thresholds for HA activation, in vitro replication in human respiratory tract cells, and in vivo mammalian pathogenicity and transmissibility were investigated. While A(H9N2) viruses from both poultry and humans exhibited features associated with mammalian adaptation, one human isolate from 2018, A/Anhui-Lujiang/39/2018, exhibited increased capacity for replication and transmission, demonstrating the pandemic potential of A(H9N2) viruses. IMPORTANCE A(H9N2) influenza viruses are widespread in poultry in many parts of the world and for over 20 years have sporadically jumped species barriers to cause human infection. As these viruses continue to diversify genetically and antigenically, it is critical to closely monitor viruses responsible for human infections, to ascertain if A(H9N2) viruses are acquiring properties that make them better suited to infect and spread among humans. In this study, we describe an active poultry surveillance system established in Vietnam to identify the scope of influenza viruses present in live bird markets and the threat they pose to human health. Assessment of a recent A(H9N2) virus isolated from an individual in China in 2018 is also reported, and it was found to exhibit properties of adaptation to humans and, importantly, it shows similarities to strains isolated from the live bird markets of Vietnam.

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In Vitro and In Vivo Models to Study the Zoonotic Mosquito-Borne Usutu Virus

Viruses ◽

10.3390/v12101116 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1116

Author(s):

Emna Benzarti ◽

Mutien Garigliany

Keyword(s):

Animal Health ◽

Neurological Complications ◽

Lessons Learned ◽

In Vivo Models ◽

Usutu Virus ◽

The Past ◽

Experimental Systems ◽

Human Infections

Usutu virus (USUV), a mosquito-borne zoonotic flavivirus discovered in South Africa in 1959, has spread to many European countries over the last 20 years. The virus is currently a major concern for animal health due to its expanding host range and the growing number of avian mass mortality events. Although human infections with USUV are often asymptomatic, they are occasionally accompanied by neurological complications reminiscent of those due to West Nile virus (another flavivirus closely related to USUV). Whilst USUV actually appears less threatening than some other emergent arboviruses, the lessons learned from Chikungunya, Dengue, and Zika viruses during the past few years should not be ignored. Further, it would not be surprising if, with time, USUV disperses further eastwards towards Asia and possibly westwards to the Americas, which may result in more pathogenic USUV strains to humans and/or animals. These observations, inviting the scientific community to be more vigilant about the spread and genetic evolution of USUV, have prompted the use of experimental systems to understand USUV pathogenesis and to boost the development of vaccines and antivirals. This review is the first to provide comprehensive coverage of existing in vitro and in vivo models for USUV infection and to discuss their contribution in advancing data concerning this neurotropic virus. We believe that this paper is a helpful tool for scientists to identify gaps in the knowledge about USUV and to design their future experiments to study the virus.

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Simian Immunodeficiency Virus SIVrcm, a Unique CCR2-Tropic Virus, Selectively Depletes Memory CD4+ T Cells in Pigtailed Macaques through Expanded Coreceptor Usage In Vivo

Journal of Virology ◽

10.1128/jvi.00444-09 ◽

2009 ◽

Vol 83 (16) ◽

pp. 7894-7908 ◽

Cited By ~ 20

Author(s):

Rajeev Gautam ◽

Thaidra Gaufin ◽

Isolde Butler ◽

Aarti Gautam ◽

Mary Barnes ◽

...

Keyword(s):

T Cells ◽

Simian Immunodeficiency Virus ◽

Effector Memory ◽

Coreceptor Usage ◽

New Host ◽

Viral Loads ◽

Immunodeficiency Virus ◽

Memory Cd4 T Cells

ABSTRACT Simian immunodeficiency virus SIVrcm, which naturally infects red-capped mangabeys (RCMs), is the only SIV that uses CCR2 as its main coreceptor due to the high frequency of a CCR5 deletion in RCMs. We investigated the dynamics of SIVrcm infection to identify specific pathogenic mechanisms associated with this major difference in SIV biology. Four pigtailed macaques (PTMs) were infected with SIVrcm, and infection was monitored for over 2 years. The dynamics of in vivo SIVrcm replication in PTMs was similar to that of other pathogenic and nonpathogenic lymphotropic SIVs. Plasma viral loads (VLs) peaked at 107 to 109 SIVrcm RNA copies/ml by day 10 postinoculation (p.i.). A viral set point was established by day 42 p.i. at 103 to 105 SIVrcm RNA copies/ml and lasted up to day 180 p.i., when plasma VLs decreased below the threshold of detection, with blips of viral replication during the follow-up. Intestinal SIVrcm replication paralleled that of plasma VLs. Up to 80% of the CD4+ T cells were depleted by day 28 p.i. in the gut. The most significant depletion (>90%) involved memory CD4+ T cells. Partial CD4+ T-cell restoration was observed in the intestine at later time points. Effector memory CD4+ T cells were the least restored. SIVrcm strains isolated from acutely infected PTMs used CCR2 coreceptor, as reported, but expansion of coreceptor usage to CCR4 was also observed. Selective depletion of effector memory CD4+ T cells is in contrast with predicted in vitro tropism of SIVrcm for macrophages and is probably due to expansion of coreceptor usage. Taken together, these findings emphasize the importance of understanding the selective forces driving viral adaptation to a new host.

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