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1.
Phytopathology ; 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38427607

RESUMEN

The image-based detection and classification of plant diseases has become increasingly important to the development of precision agriculture. We consider the case of tomato, a high-value crop supporting the livelihoods of many farmers around the world. Many biotic and abiotic plant health issues impede the efficient production of this crop, and laboratory-based diagnostics are inaccessible in many remote regions. Early detection of these plant health issues is essential for efficient and accurate response, prompting exploration of alternatives for field detection. Considering the availability of low-cost smartphones, artificial intelligence-based classification facilitated by mobile phone imagery can be a practical option. This study introduces a smartphone-attachable 30x microscopic lens, used to produce the novel tomato microimaging dataset of 8500 images representing 34 tomato plant conditions on the upper and lower sides of leaves as well as on the surface of tomato fruits. We introduce TOMMicroNet, a 14-layer convolutional neural network (CNN) trained to classify amongst biotic and abiotic plant health issues, and we compare it against six existing pre-trained CNN models. We compared two separate pipelines of grouping data for training TOMMicroNet, either presenting all data at once or separating into subsets based on the three parts of the plant. Comparing configurations based on cross-validation and F1 scores, we determined that TOMMicroNet attained the highest performance when trained on the complete dataset, with 95% classification accuracy on both training and external datasets. Given TOMMicroNet's capabilities when presented with unfamiliar data, this approach has the potential for the identification of plant health issues.

2.
QJM ; 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38377410

RESUMEN

Chikungunya virus, an arthropod-borne pathogen is recognised by the World Health Organization as a top priority Emerging Infectious Disease and is ranked fourth in public health needs according to the Coalition for Epidemic Preparedness Innovations (CEPI). Despite its substantial impact, as evidenced by an annual estimate of 120,274 disability-adjusted life years, our understanding of the chronic aspects of chikungunya disease remains limited. This review focuses on Chronic Chikungunya Disease (CCD), emphasising its clinical manifestations, immunopathogenesis, therapeutic options, and disease burden.

3.
J Gen Virol ; 105(2)2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38421278

RESUMEN

Background. Chikungunya virus (CHIKV) causes chikungunya fever and has been responsible for major global epidemics of arthritic disease over the past two decades. Multiple CHIKV vaccine candidates are currently undergoing or have undergone human clinical trials, with one vaccine candidate receiving FDA approval. This scoping review was performed to evaluate the 'efficacy', 'safety' and 'duration of protection' provided by CHIKV vaccine candidates in human clinical trials.Methods. This scoping literature review addresses studies involving CHIKV vaccine clinical trials using available literature on the PubMed, Medline Embase, Cochrane Library and Clinicaltrial.gov databases published up to 25 August 2023. Covidence software was used to structure information and review the studies included in this article.Results. A total of 1138 studies were screened and, after removal of duplicate studies, 12 relevant studies were thoroughly reviewed to gather information. This review summarizs that all seven CHIKV vaccine candidates achieved over 90 % seroprotection against CHIKV after one or two doses. All vaccines were able to provide neutralizing antibody protection for at least 28 days.Conclusions. A variety of vaccine technologies have been used to develop CHIKV vaccine candidates. With one vaccine candidate having recently received FDA approval, it is likely that further CHIKV vaccines will be available commercially in the near future.


Asunto(s)
Fiebre Chikungunya , Virus Chikungunya , Vacunas Virales , Humanos , Vacunas Virales/efectos adversos , Fiebre Chikungunya/prevención & control , Anticuerpos Neutralizantes , Bases de Datos Factuales
4.
Nat Commun ; 14(1): 6605, 2023 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-37884534

RESUMEN

Arthritogenic alphaviruses are positive-strand RNA viruses that cause debilitating musculoskeletal diseases affecting millions worldwide. A recent discovery identified the four-and-a-half-LIM domain protein 1 splice variant A (FHL1A) as a crucial host factor interacting with the hypervariable domain (HVD) of chikungunya virus (CHIKV) nonstructural protein 3 (nsP3). Here, we show that acute and chronic chikungunya disease in humans correlates with elevated levels of FHL1. We generated FHL1-/- mice, which when infected with CHIKV or o'nyong-nyong virus (ONNV) displayed reduced arthritis and myositis, fewer immune infiltrates, and reduced proinflammatory cytokine/chemokine outputs, compared to infected wild-type (WT) mice. Interestingly, disease signs were comparable in FHL1-/- and WT mice infected with arthritogenic alphaviruses Ross River virus (RRV) or Mayaro virus (MAYV). This aligns with pull-down assay data, which showed the ability of CHIKV and ONNV nsP3 to interact with FHL1, while RRV and MAYV nsP3s did not. We engineered a CHIKV mutant unable to bind FHL1 (CHIKV-ΔFHL1), which was avirulent in vivo. Following inoculation with CHIKV-ΔFHL1, mice were protected from disease upon challenge with CHIKV and ONNV, and viraemia was significantly reduced in RRV- and MAYV-challenged mice. Targeting FHL1-binding as an approach to vaccine design could lead to breakthroughs in mitigating alphaviral disease.


Asunto(s)
Artritis , Fiebre Chikungunya , Virus Chikungunya , Vacunas , Animales , Humanos , Ratones , Artritis/genética , Fiebre Chikungunya/prevención & control , Péptidos y Proteínas de Señalización Intracelular , Proteínas con Dominio LIM/genética , Proteínas Musculares/genética , Virus O'nyong-nyong
5.
Vaccine ; 41(27): 3976-3988, 2023 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-37230889

RESUMEN

Mosquito-transmitted chikungunya virus (CHIKV) is the causal pathogen of CHIKV disease and is responsible for global epidemics of arthritic disease. CHIKV infection can lead to severe chronic and debilitating arthralgia, significantly impacting patient mobility and quality of life. Our previous studies have shown a live-attenuated CHIKV vaccine candidate, CHIKV-NoLS, to be effective in protecting against CHIKV disease in mice vaccinated with one dose. Further studies have demonstrated the value of a liposome RNA delivery system to deliver the RNA genome of CHIKV-NoLS directly in vivo, promoting de novo production of live-attenuated vaccine particles in vaccinated hosts. This system, designed to bypass live-attenuated vaccine production bottlenecks, uses CAF01 liposomes. However, one dose of CHIKV-NoLS CAF01 failed to provide systemic protection against CHIKV challenge in mice, with low levels of CHIKV-specific antibodies. Here we describe CHIKV-NoLS CAF01 booster vaccination regimes designed to increase vaccine efficacy. C57BL/6 mice were vaccinated with three doses of CHIKV-NoLS CAF01 either intramuscularly or subcutaneously. CHIKV-NoLS CAF01 vaccinated mice developed a systemic immune response against CHIKV that shared similarity to vaccination with CHIKV-NoLS, including high levels of CHIKV-specific neutralising antibodies in subcutaneously inoculated mice. CHIKV-NoLS CAF01 vaccinated mice were protected against disease signs and musculoskeletal inflammation when challenged with CHIKV. Mice given one dose of live-attenuated CHIKV-NoLS developed a long lasting protective immune response for up to 71 days. A clinically relevant CHIKV-NoLS CAF01 booster regime can overcome the challenges faced by our previous one dose strategy and provide systemic protection against CHIKV disease.


Asunto(s)
Fiebre Chikungunya , Virus Chikungunya , Vacunas Virales , Ratones , Animales , Liposomas , Vacunas Atenuadas , Calidad de Vida , Ratones Endogámicos C57BL , Anticuerpos Antivirales
6.
Vaccine ; 41(20): 3171-3177, 2023 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-37088603

RESUMEN

The widespread outbreak of the monkeypox virus (MPXV) recognized in 2022 poses new challenges for public healthcare systems worldwide. With more than 86,000 people infected, there is concern that MPXV may become endemic outside of its original geographical area leading to repeated human spillover infections or continue to be spread person-to-person. Fortunately, classical public health measures (e.g., isolation, contact tracing and quarantine) and vaccination have blunted the spread of the virus, but cases are continuing to be reported in 28 countries in March 2023. We describe here the vaccines and drugs available for the prevention and treatment of MPXV infections. However, although their efficacy against monkeypox (mpox) has been established in animal models, little is known about their efficacy in the current outbreak setting. The continuing opportunity for transmission raises concerns about the potential for evolution of the virus and for expansion beyond the current risk groups. The priorities for action are clear: 1) more data on the efficacy of vaccines and drugs in infected humans must be gathered; 2) global collaborations are necessary to ensure that government authorities work with the private sector in developed and low and middle income countries (LMICs) to provide the availability of treatments and vaccines, especially in historically endemic/enzootic areas; 3) diagnostic and surveillance capacity must be increased to identify areas and populations where the virus is present and may seed resurgence; 4) those at high risk of severe outcomes (e.g., immunocompromised, untreated HIV, pregnant women, and inflammatory skin conditions) must be informed of the risk of infection and be protected from community transmission of MPXV; 5) engagement with the hardest hit communities in a non-stigmatizing way is needed to increase the understanding and acceptance of public health measures; and 6) repositories of monkeypox clinical samples, including blood, fluids, tissues and lesion material must be established for researchers. This MPXV outbreak is a warning that pandemic preparedness plans need additional coordination and resources. We must prepare for continuing transmission, resurgence, and repeated spillovers of MPXV.


Asunto(s)
Vacunas , Embarazo , Animales , Humanos , Femenino , /prevención & control , Virus de la Viruela de los Monos , Vacunación , Brotes de Enfermedades/prevención & control
7.
mBio ; 14(2): e0058823, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37036079

RESUMEN

Arthritogenic alphaviruses such as Ross River virus (RRV) and Chikungunya virus (CHIKV) are responsible for large-scale epidemics that cause debilitating acute and chronic musculoskeletal diseases. MXRA8 was recently discovered as an entry receptor for multiple alphaviruses including CHIKV, RRV, Mayaro virus (MAYV), and O'nyong-nyong virus (ONNV). However, the role of MXRA8 in the development of alphavirus-induced musculoskeletal inflammation has not yet been fully studied. Here, we attempt to fully characterize the contribution of MXRA8 to RRV disease in an established mouse model. MXRA8 knockout (MXRA8-/-) mice generated on a C57BL/6J background, showed abrogated disease signs and reduced viral replication, which correlated with lower viral load, diminished proinflammatory cytokines, and limited cell infiltrates in inflamed tissues. Immunomodulation genes were upregulated to higher levels in RRV-infected wild-type (WT) mice than in MXRA8-/- mice. Intriguingly, Cdkn1a and Ifi44 genes in blood and CD127/IL7RA, CD45, BatF3, IFNGR, Ly6G/Ly6C, CD40, CD127, F4/80, and MHC-II genes in quadriceps were found to be upregulated in RRV-infected MXRA8-/- mice compared to WT mice. Our results showed an essential role of MXRA8 in the immune response of mice infected with RRV and, more importantly, demonstrated novel changes in immunomodulation genes, which shed light on the immunopathogenesis of alphavirus-induced disease. IMPORTANCE Previous studies have shown the importance of the cell surface protein MXRA8 as an entry receptor for several different prominent alphaviruses such as CHIKV, RRV, MAYV, and ONNV. In particular, the role of MXRA8 in the tissue tropism, viral pathogenesis, and immune response of a CHIKV mouse model have already been briefly characterized. However, the role of MXRA8 warrants further characterization in RRV disease background, since there are noticeable differences in the disease profile between CHIKV and RRV. For example, patients infected with CHIKV are usually affected by sudden onset of severe arthritis and fever, whereas RRV-infected patients generally only have minor joint pain and mild fever. Here, we characterized the role of MXRA8 in RRV disease and assessed several key mechanisms of MXRA8 that may contribute to the disease progression.


Asunto(s)
Infecciones por Alphavirus , Artritis , Virus Chikungunya , Animales , Ratones , Virus del Río Ross/genética , Ratones Endogámicos C57BL , Virus Chikungunya/genética , Inmunoglobulinas , Proteínas de la Membrana/metabolismo
8.
Front Immunol ; 14: 1030879, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36845136

RESUMEN

Introduction: There is an unmet medical need for effective anti-inflammatory agents for the treatment of acute and post-acute lung inflammation caused by respiratory viruses. The semi-synthetic polysaccharide, Pentosan polysulfate sodium (PPS), an inhibitor of NF-kB activation, was investigated for its systemic and local anti-inflammatory effects in a mouse model of influenza virus A/PR8/1934 (PR8 strain) mediated infection. Methods: Immunocompetent C57BL/6J mice were infected intranasally with a sublethal dose of PR8 and treated subcutaneously with 3 or 6 mg/kg PPS or vehicle. Disease was monitored and tissues were collected at the acute (8 days post-infection; dpi) or post-acute (21 dpi) phase of disease to assess the effect of PPS on PR8-induced pathology. Results: In the acute phase of PR8 infection, PPS treatment was associated with a reduction in weight loss and improvement in oxygen saturation when compared to vehicle-treated mice. Associated with these clinical improvements, PPS treatment showed a significant retention in the numbers of protective SiglecF+ resident alveolar macrophages, despite uneventful changes in pulmonary leukocyte infiltrates assessed by flow cytometry. PPS treatment in PR8- infected mice showed significant reductions systemically but not locally of the inflammatory molecules, IL-6, IFN-g, TNF-a, IL-12p70 and CCL2. In the post-acute phase of infection, PPS demonstrated a reduction in the pulmonary fibrotic biomarkers, sICAM-1 and complement factor C5b9. Discussion: The systemic and local anti-inflammatory actions of PPS may regulate acute and post-acute pulmonary inflammation and tissue remodeling mediated by PR8 infection, which warrants further investigation.


Asunto(s)
Neumonía , Ratones , Animales , Poliéster Pentosan Sulfúrico/farmacología , Poliéster Pentosan Sulfúrico/uso terapéutico , Ratones Endogámicos C57BL , Neumonía/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad
9.
Br J Pharmacol ; 180(2): 133-143, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36394425

RESUMEN

A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis-associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The coronavirus disease 2019 (COVID-19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS-CoV-2-induced ARDS at the infective and post-infective stages. In this minireview, we examine drugs targeting IL-1ß, IL-4/IL-13, IL-6 and TNF-α tested in COVID-19 patients.


Asunto(s)
COVID-19 , Síndrome de Dificultad Respiratoria , Humanos , SARS-CoV-2 , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Reposicionamiento de Medicamentos , Citocinas
10.
Nat Commun ; 13(1): 7675, 2022 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-36509737

RESUMEN

Although ocular manifestations are reported in patients with COVID-19, consensus on ocular tropism of SARS-CoV-2 is lacking. Here, we infect K18-hACE2 transgenic mice with SARS-CoV-2 using various routes. We observe ocular manifestation and retinal inflammation with production of pro-inflammatory cytokines in the eyes of intranasally (IN)-infected mice. Intratracheal (IT) infection results in dissemination of the virus from the lungs to the brain and eyes via trigeminal and optic nerves. Ocular and neuronal invasions are confirmed using intracerebral (IC) infection. Notably, the eye-dropped (ED) virus does not cause lung infection and becomes undetectable with time. Ocular and neurotropic distribution of the virus in vivo is evident in fluorescence imaging with an infectious clone of SARS-CoV-2-mCherry. The ocular tropic and neuroinvasive characteristics of SARS-CoV-2 are confirmed in wild-type Syrian hamsters. Our data can improve the understanding regarding viral transmission and clinical characteristics of SARS-CoV-2 and help in improving COVID-19 control procedures.


Asunto(s)
COVID-19 , SARS-CoV-2 , Cricetinae , Ratones , Animales , Modelos Animales de Enfermedad , Ratones Transgénicos , Pulmón , Mesocricetus , Inflamación
12.
J Virol ; 96(17): e0099922, 2022 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-36000846

RESUMEN

Arthritogenic alphaviruses are mosquito-borne arboviruses that include several re-emerging human pathogens, including the chikungunya (CHIKV), Ross River (RRV), Mayaro (MAYV), and o'nyong-nyong (ONNV) virus. Arboviruses are transmitted via a mosquito bite to the skin. Herein, we describe intradermal RRV infection in a mouse model that replicates the arthritis and myositis seen in humans with Ross River virus disease (RRVD). We show that skin infection with RRV results in the recruitment of inflammatory monocytes and neutrophils, which together with dendritic cells migrate to draining lymph nodes (LN) of the skin. Neutrophils and monocytes are productively infected and traffic virus from the skin to LN. We show that viral envelope N-linked glycosylation is a key determinant of skin immune responses and disease severity. RRV grown in mammalian cells elicited robust early antiviral responses in the skin, while RRV grown in mosquito cells stimulated poorer early antiviral responses. We used glycan mass spectrometry to characterize the glycan profile of mosquito and mammalian cell-derived RRV, showing deglycosylation of the RRV E2 glycoprotein is associated with curtailed skin immune responses and reduced disease following intradermal infection. Altogether, our findings demonstrate skin infection with an arthritogenic alphavirus leads to musculoskeletal disease and envelope glycoprotein glycosylation shapes disease outcome. IMPORTANCE Arthritogenic alphaviruses are transmitted via mosquito bites through the skin, potentially causing debilitating diseases. Our understanding of how viral infection starts in the skin and how virus systemically disseminates to cause disease remains limited. Intradermal arbovirus infection described herein results in musculoskeletal pathology, which is dependent on viral envelope N-linked glycosylation. As such, intradermal infection route provides new insights into how arboviruses cause disease and could be extended to future investigations of skin immune responses following infection with other re-emerging arboviruses.


Asunto(s)
Infecciones por Alphavirus , Artritis , Miositis , Polisacáridos , Virus del Río Ross , Piel , Infecciones por Alphavirus/complicaciones , Infecciones por Alphavirus/inmunología , Animales , Antivirales/inmunología , Artritis/complicaciones , Artritis/inmunología , Culicidae/virología , Células Dendríticas , Modelos Animales de Enfermedad , Glicosilación , Humanos , Espectrometría de Masas , Ratones , Monocitos , Miositis/complicaciones , Miositis/inmunología , Neutrófilos , Polisacáridos/química , Polisacáridos/inmunología , Virus del Río Ross/inmunología , Piel/inmunología , Piel/virología , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/inmunología
13.
mBio ; 13(3): e0068322, 2022 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-35420469

RESUMEN

Compared to the original ancestral strain of SARS-CoV-2, the Delta variant of concern has shown increased transmissibility and resistance toward COVID-19 vaccines and therapies. However, the pathogenesis of the disease associated with Delta is still not clear. In this study, using K18-hACE2 transgenic mice, we assessed the pathogenicity of the Delta variant by characterizing the immune response following infection. We found that Delta induced the same clinical disease manifestations as the ancestral SARS-CoV-2, but with significant dissemination to multiple tissues, such as brain, intestine, and kidney. Histopathological analysis showed that tissue pathology and cell infiltration in the lungs of Delta-infected mice were the same as in mice infected with the ancestral SARS-CoV-2. Delta infection caused perivascular inflammation in the brain and intestinal wall thinning in K18-hACE2 transgenic mice. Increased cell infiltration in the kidney was observed in both ancestral strain- and Delta-infected mice, with no clear visible tissue damage identified in either group. Interestingly, compared with mice infected with the ancestral strain, the numbers of CD45+ cells, T cells, B cells, inflammatory monocytes, and dendritic cells were all significantly lower in the lungs of the Delta-infected mice, although there was no significant difference in the levels of proinflammatory cytokines between the two groups. Our results showed distinct immune response patterns in the lungs of K18-hACE2 mice infected with either the ancestral SARS-CoV-2 or Delta variant of concern, which may help to guide therapeutic interventions for emerging SARS-CoV-2 variants. IMPORTANCE SARS-CoV-2 variants, with the threat of increased transmissibility, infectivity, and immune escape, continue to emerge as the COVID-19 pandemic progresses. Detailing the pathogenesis of disease caused by SARS-CoV-2 variants, such as Delta, is essential to better understand the clinical threat caused by emerging variants and associated disease. This study, using the K18-hACE2 mouse model of severe COVID-19, provides essential observation and analysis on the pathogenicity and immune response of Delta infection. These observations shed light on the changing disease profile associated with emerging SARS-CoV-2 variants and have potential to guide COVID-19 treatment strategies.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Hepatitis D , Animales , Vacunas contra la COVID-19 , Modelos Animales de Enfermedad , Humanos , Melfalán , Ratones , Ratones Transgénicos , Pandemias , SARS-CoV-2/genética , gammaglobulinas
14.
mBio ; 13(2): e0028922, 2022 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-35254128

RESUMEN

Alphaviral arthritides caused by mosquito-borne arboviruses such as chikungunya virus (CHIKV) can persist for months after the initial acute disease. Here, we investigated the contribution of interleukin-17 (IL-17), a cytokine involved in chronic autoimmune arthropathies such as rheumatoid arthritis, to the development of alphaviral arthropathy. Sera from CHIKV-infected patients who displayed both acute and chronic disease showed high levels of IL-17, IL-6, IL-21, IL-22, and IL-23, especially during the chronic phase of disease. We sought to validate these findings using a mouse model of CHIKV infection and disease using wild-type and IL-17A-deficient mice. Mice were infected with CHIKV, and joint and muscle tissues were harvested at designated time points. Tissue infiltrates were examined by immunohistochemistry, and tissue mRNA and protein expression of cytokines was assessed. Joint and muscle pathology was assessed using histology. CHIKV-infected mice lacking IL-17A showed reduced tissue inflammation and neutrophil infiltration, compared to wild-type mice. These investigations showed a role for IL-17 in the acute phase of CHIKV infection and also during the postacute disease resolution phase. IMPORTANCE CHIKV has been prevalent in Africa, Asia, and the Indian Ocean Islands for decades. There are currently no clinically approved vaccines or specific antiviral drugs targeting CHIKV. The upregulation of IL-17 detected in CHIKV disease patients and the reduced disease seen in IL-17-deficient mice suggest a correlation between IL-17 signaling pathways and CHIKV-induced arthritic inflammation. With an established role in contributing to the pathogenesis of immune-mediated diseases, such as psoriatic arthritis and rheumatoid arthritis, IL-17 signaling plays an important role in alphavirus arthritides.


Asunto(s)
Artritis Reumatoide , Fiebre Chikungunya , Virus Chikungunya , Interleucina-17/metabolismo , Animales , Virus Chikungunya/genética , Citocinas , Humanos , Inflamación , Ratones
15.
PLoS Pathog ; 18(2): e1010185, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35143591

RESUMEN

Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17-producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy.


Asunto(s)
Artritis Reumatoide/inmunología , Inmunidad Celular , Inflamación/inmunología , Interleucina-17/inmunología , Miositis/inmunología , Virus del Río Ross/inmunología , Infecciones por Alphavirus/inmunología , Infecciones por Alphavirus/virología , Animales , Artritis Reumatoide/virología , Chlorocebus aethiops , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Miositis/virología , Células Vero , Carga Viral
16.
mBio ; 13(1): e0336321, 2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35089088

RESUMEN

Ross River virus (RRV) is the major mosquito-borne virus in the South Pacific region. RRV infections are characterized by arthritic symptoms, which can last from several weeks to months. Type I interferon (IFN), the primary antiviral innate immune response, is able to modulate adaptive immune responses. The relationship between the protective role of type I IFN and the induction of signaling proteins that drive RRV disease pathogenesis remains poorly understood. In the present study, the role of TIR-domain-containing adapter-inducing interferon-ß (TRIF), an essential signaling adaptor protein downstream of Toll-like receptor (TLR) 3, a key single-stranded RNA (ssRNA)-sensing receptor, was investigated. We found that TRIF-/- mice were highly susceptible to RRV infection, with severe disease, high viremia, and a low type I IFN response early during disease development, which suggests the TLR3-TRIF axis may engage early in response to RRV infection. The number and the activation level of CD4+ T cells, CD8+ T cells, and NK cells were reduced in TRIF-/- mice compared to those in infected wild-type (WT) mice. In addition, the number of germinal center B cells was lower in TRIF-/- mice than WT mice following RRV infection, with lower titers of IgG antibodies detected in infected TRIF-/- mice compared to WT. Interestingly, the requirement for TRIF to promote immunoglobulin class switch recombination was at the level of the local immune microenvironment rather than B cells themselves. The slower resolution of RRV disease in TRIF-/- mice was associated with persistence of the RRV genome in muscle tissue and a continuing IFN response. IMPORTANCE RRV has been prevalent in the South Pacific region for decades and causes substantial economic and social costs. Though RRV is geographically restricted, a number of other alphaviruses have spread globally due to expansion of the mosquito vectors and increased international travel. Since over 30 species of mosquitoes have been implicated as potent vectors for RRV dissemination, RRV has the potential to further expand its distribution. In the pathogenesis of RRV disease, it is still not clear how innate immune responses synergize with adaptive immune responses. Type I IFN is crucial for bridging innate to adaptive immune responses to viral invasion. Hence, key signaling proteins in type I IFN induction pathways, which are important for type I IFN modulation, may also play critical roles in viral pathogenesis. This study provides insight into the role of TRIF in RRV disease development.


Asunto(s)
Infecciones por Alphavirus , Interferón Tipo I , Ratones , Animales , Antivirales , Virus del Río Ross/genética , Linfocitos T CD8-positivos/metabolismo , Mosquitos Vectores , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Interferón beta , Ratones Noqueados
17.
mSphere ; 6(5): e0065921, 2021 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-34585962

RESUMEN

Infection with mosquito-borne arthritogenic alphaviruses, such as Ross River virus (RRV) and Barmah Forest virus (BFV), can lead to long-lasting rheumatic disease. Existing mouse models that recapitulate the disease signs and immunopathogenesis of acute RRV and BFV infection have consistently shown relevance to human disease. However, these mouse models, which chiefly model hindlimb dysfunction, may be prone to subjective interpretation when scoring disease. Assessment is therefore time-consuming and requires experienced users. The DigiGait system provides video-based measurements of movement, behavior, and gait dynamics in mice and small animals. Previous studies have shown DigiGait to be a reliable system to objectively quantify changes in gait in other models of pain and inflammation. Here, for the first time, we determine measurable differences in the gait of mice with infectious arthritis using the DigiGait system. Statistically significant differences in paw area and paw angle were detected during peak disease in RRV-infected mice. Significant differences in temporal gait parameters were also identified during the period of peak disease in RRV-infected mice. These trends were less obvious or absent in BFV-infected mice, which typically present with milder disease signs than RRV-infected mice. The DigiGait system therefore provides an objective model of variations in gait dynamics in mice acutely infected with RRV. DigiGait is likely to have further utility for murine models that develop severe forms of infectious arthritis resulting in hindlimb dysfunction like RRV. IMPORTANCE Mouse models that accurately replicate the immunopathogenesis and clinical disease of alphavirus infection are vital to the preclinical development of therapeutic strategies that target alphavirus infection and disease. Current models rely on subjective scoring made through experienced observation of infected mice. Here, we demonstrate how the DigiGait system, and interventions on mice to use this system, can make an efficient objective assessment of acute disease progression and changes in gait in alphavirus-infected mice. Our study highlights the importance of measuring gait parameters in the assessment of models of infectious arthritis.


Asunto(s)
Infecciones por Alphavirus/virología , Artritis Infecciosa/fisiopatología , Artritis Infecciosa/virología , Análisis de la Marcha/veterinaria , Virus del Río Ross/fisiología , Infecciones por Alphavirus/patología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Virus del Río Ross/patogenicidad , Carrera , Caminata
18.
mBio ; 12(2)2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879586

RESUMEN

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development.IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit's value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.


Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , COVID-19/etiología , SARS-CoV-2/patogenicidad , Animales , COVID-19/patología , COVID-19/virología , Síndrome de Liberación de Citoquinas/etiología , Modelos Animales de Enfermedad , Femenino , Interacciones Microbiota-Huesped , Humanos , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Masculino , Ratones , Ratones Transgénicos , Pandemias , Neumonía Viral/etiología , Neumonía Viral/virología , Genética Inversa/métodos , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Tropismo Viral , Replicación Viral
19.
mBio ; 12(1)2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563817

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the globe at unprecedented speed and is showing no signs of slowing down. The outbreak of coronavirus disease 2019 (COVID-19) has led to significant health burden in infected patients especially in those with underlying comorbidities. The aim of this study was to evaluate the correlation between comorbidities and their role in the exacerbation of disease in COVID-19 patients leading to fatal outcomes. A systematic review was conducted using data from MEDLINE, Scopus, Web of Science, and EMBASE databases published from 1 December 2019 to 15 September 2020. Fifty-three articles were included in the systematic review. Of those 53 articles, 8 articles were eligible for meta-analysis. Hypertension, obesity, and diabetes mellitus were identified to be the most prevalent comorbidities in COVID-19 patients. Our meta-analysis showed that cancer, chronic kidney diseases, diabetes mellitus, and hypertension were independently associated with mortality in COVID-19 patients. Chronic kidney disease was statistically the most prominent comorbidity leading to death. However, despite having high prevalence, obesity was not associated with mortality in COVID-19 patients.IMPORTANCE COVID-19 has plagued the world since it was first identified in December 2019. Previous systematic reviews and meta-analysis were limited by various factors such as the usage of non-peer reviewed data and were also limited by the lack of clinical data on a global scale. Comorbidities are frequently cited as risk factors for severe COVID-19 outcomes. However, the degree to which specific comorbidities impact the disease is debatable. Our study selection involves a global reach and covers all comorbidities that were reported to be involved in the exacerbation of COVID-19 leading to fatal outcomes, which allows us to identify the specific comorbidities that have higher risk in patients. The study highlights COVID-19 high-risk groups. However, further research should focus on the status of comorbidities and prognosis in COVID-19 patients.


Asunto(s)
COVID-19/epidemiología , SARS-CoV-2 , COVID-19/mortalidad , COVID-19/patología , Comorbilidad , Hospitalización , Humanos , Prevalencia , Factores de Riesgo , Resultado del Tratamiento
20.
J Gen Virol ; 102(3)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33410734

RESUMEN

The complement alternative pathway (AP) is tightly regulated and changes in two important AP components, factor B (FB) and factor H (FH) are linked to severe dengue in humans. Here, a mouse model of dengue was investigated to define the changes in FB and FH and assess the utility of this model to study the role of the AP in severe dengue. Throughout the period of viremia in the AG129 IFN signalling-deficient mouse, an increase in FB and a decrease in FH was observed following dengue virus (DENV) infection, with the former only seen in a model of more severe disease associated with antibody-dependent enhancement (ADE). Terminal disease was associated with a decrease in FB and FH, with greater changes during ADE, and accompanied by increased C3 degradation consistent with complement activation. In silico analysis of NFκΒ, signal transducer and activator of transcription (STAT) and IFN-driven FB and FH promoter elements to reflect the likely impact of the lack of IFN-responses in AG129 mice, demonstrated that these elements differed markedly between human and mouse, notably with mouse FH lacking NFκΒ and key IFN-stimulated response elements (ISRE), and FB with many more NFκΒ and STAT-responsive elements than human FB. Thus, the AG129 mouse offers utility in demonstrating changes in FB and FH that, similar to humans, are associated with severe disease, but lack predicted important human-specific and IFN-dependent responses of FB and FH to DENV-infection that are likely to regulate the subtleties of the overall AP response during dengue disease in humans.


Asunto(s)
Factor B del Complemento/metabolismo , Factor H de Complemento/metabolismo , Vía Alternativa del Complemento , Dengue/inmunología , Dengue Grave/inmunología , Animales , Acrecentamiento Dependiente de Anticuerpo , Factor B del Complemento/genética , Factor H de Complemento/genética , Dengue/virología , Virus del Dengue/inmunología , Virus del Dengue/fisiología , Modelos Animales de Enfermedad , Humanos , Interferones/metabolismo , Ratones , Regiones Promotoras Genéticas , Dengue Grave/virología , Viremia
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