Virus Infection Model Research Articles

Armstrong strain lymphocytic choriomeningitis virus infection after accidental laboratory exposure

BackgroundLymphocytic choriomeningitis virus (LCMV) is a human pathogen naturally present in wild rodents. In addition, LCMV is routinely used in immunology research as a model of viral infection in mice. The Armstrong common laboratory strain and the Clone-13 variant induce acute and chronic infections in mice, respectively. The frequent use of this virus in laboratory settings is associated with a risk of human infection for laboratory personnel. In contrast to LCMV Clone-13, few human laboratory infections with LCMV Armstrong have been reported, leading to a poor understanding of symptoms related to infection with this specific LCMV strain.Case presentationA researcher accidentally infected herself percutaneously with LCMV Armstrong. Symptoms including headaches, dizziness, eye pain and nausea appeared seven days post-exposure and lasted ten days. LCMV-IgM antibodies were detected at 28 days post-infection and IgG seroconversion was observed later. Complete recovery was confirmed three months post exposure.ConclusionsResearch involving live viruses comes with the risk of infection for research personnel. This case is the first reported accidental human infection with LCMV Armstrong. The symptoms differed from reported infections with LCMV Clone-13, by the absence of fever and vomiting, and presence of leg numbness. This report will therefore help clinicians and public health authorities to recognize the symptoms associated with LCMV Armstrong infections and to offer appropriate counselling to individuals who accidentally expose themselves.

A quantitative model for virus uncoating predicts influenza A infectivity

For virus infection of new host cells, the disassembly of the protective outer protein shell (capsid) is a critical step, but the mechanisms and host-virus interactions underlying the dynamic, active, and regulated uncoating process are largely unknown. Here, we develop an experimentally supported, multiscale kinetics model that elucidates mechanisms of influenza A virus (IAV) uncoating in cells. Biophysical modeling demonstrates that interactions between capsid M1 proteins, host histone deacetylase 6 (HDAC6), and molecular motors can physically break the capsid in a tug-of-war mechanism. Biochemical analysis and biochemical-biophysical modeling identify unanchored ubiquitin chains as essential and allow robust prediction of uncoating efficiency in cells. Remarkably, the different infectivity of two clinical strains can be ascribed to a single amino acid variation in M1 that affects binding to HDAC6. By identifying crucial modules of viral infection kinetics, the mechanisms and models presented here could help formulate novel strategies for broad-range antiviral treatment.

Automated control of the immune response to the causants of infectious disease

The problems that arose as a result of the rapid spread of the new coronavirus infection COVID-19 and the inability of health care institutions to provide the necessary medical care to a large number of patients in a timely manner showed the need to develop new approaches to diagnosis and the formation of an individual treatment program. Important in this direction is the development and implementation of specialized decision support systems based on the integration of expert systems for the analysis and interpretation of medical data and mathematical modeling tools. In order to form effective treatment programs, it is necessary to ensure the availability of reliable tools for predicting the dynamics of the disease in the conditions of external medical influences, various protection mechanisms, spatial effects, mixed infections etc. The purpose of this work is to generalize the basic model of viral infection to predict the complex controlled influence of adsorption and immune therapy on the development of the disease, taking into account diffusion disturbance and temperature response of the body, which is an important element of specialized decision-making systems for the formation of effective treatment programs. To find the solution of the original model singularly perturbed problem with delays, the procedure of stepwise numerical asymptotic approximation of the solutions of the corresponding specially constructed sequence of problems without delay has been modernized. Based on the obtained results of computer modeling, it was confirmed that the introduction of adsorbents during periods of intensive growth of the number of viral elements makes it possible to sufficiently effectively reduce the rate of their reproduction, and, therefore, provides an additional way of controlling the number of antigens in the body and preventing their supercritical growth. It is emphasized that taking into account the features of the action of adsorption drugs is important for making optimized decisions regarding the use of adsorption therapy

Lipin-2 regulates the antiviral and anti-inflammatory responses to interferon.

Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet characterized. Here, we reveal that lipin-2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT-1-dependent manner. Lipin-2 inhibits viral replication both in vitro and in vivo. Moreover, lipin-2 also acts as a regulator of inflammation in a viral context by reducing the signaling through TLR3 and the generation of ROS and release of mtDNA that ultimately activate the NLRP3 inflammasome. Inhibitors of mtDNA release from mitochondria restrict IL-1β production in lipin-2-deficient animals in a model of viral infection. Finally, analyses of databases from COVID-19 patients show that LPIN2 expression levels negatively correlate with the severity of the disease. Overall, these results uncover novel regulatory mechanisms of the IFN response driven by lipin-2 and open new perspectives for the future management of patients with LPIN2 mutations.

SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2r+CD8+ T cells and NKG2Alo natural killer (NK) cells and was further increased in NKG2Alo NK cells after spike protein stimulation. However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition. Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ.

A novel approach to state estimation of HIV infection dynamics using fixed-time fractional order observer

This paper presents a novel approach to designing a fixed-time fractional order observer for estimating the states of the dynamic model of human immunodeficiency virus (HIV) infection. The proposed approach combines output injection terminal sliding mode and RBF neural network strategies to achieve a robust and efficient estimation of the states of the HIV model within a fixed time frame. The main contributions of this work are the introduction of an output injection observer that ensures the stability of the error system along with a novel nonlinear sliding surface that guarantees the fixed-time error convergence to the neighborhood of zero. Moreover, the closed-loop scheme of the observer design is proven to be bounded, and the fixed-time stability of the observer error is obtained using the fractional Lyapunov stability approach. Simulation results show that the proposed fixed-time fractional order observer design provides accurate and efficient estimation of the states of the HIV model.

Mathematical analysis of the transmission dynamics of viral infection with effective control policies via fractional derivative

Abstract It is well known that viral infections have a high impact on public health in multiple ways, including disease burden, outbreaks and pandemic, economic consequences, emergency response, strain on healthcare systems, psychological and social effects, and the importance of vaccination. Mathematical models of viral infections help policymakers and researchers to understand how diseases can spread, predict the potential impact of interventions, and make informed decisions to control and manage outbreaks. In this work, we formulate a mathematical model for the transmission dynamics of COVID-19 in the framework of a fractional derivative. For the analysis of the recommended model, the fundamental concepts and results are presented. For the validity of the model, we have proven that the solutions of the recommended model are positive and bounded. The qualitative and quantitative analyses of the proposed dynamics have been carried out in this research work. To ensure the existence and uniqueness of the proposed COVID-19 dynamics, we employ fixed-point theorems such as Schaefer and Banach. In addition to this, we establish stability results for the system of COVID-19 infection through mathematical skills. To assess the influence of input parameters on the proposed dynamics of the infection, we analyzed the solution pathways using the Laplace Adomian decomposition approach. Moreover, we performed different simulations to conceptualize the role of input parameters on the dynamics of the infection. These simulations provide visualizations of key factors and aid public health officials in implementing effective measures to control the spread of the virus.

A Strainer-Based Platform for the Collection and Immunolabeling of Porcine Epidemic Diarrhea Virus-Infected Porcine Intestinal Organoid.

The development of organoid research has raised new requirements for this methodology. In a previous study, we demonstrated that an emerging protocol achieved the collection, loading, and programmed immunolabeling of mouse intestinal organoids based on a strainer platform. To uncover the applied potential of this novel methodology on organoids from other species, the strainer platform was utilized to characterize the porcine epidemic diarrhea virus (PEDV)-infected porcine intestinal organoid model. Based on a previous study, some steps were changed to improve the efficiency of the assay by simplifying the reagent addition procedure. In addition, we redefined the range of strainer sizes on porcine intestinal organoids, showing that strainers with pore sizes of 40 and 70 μm matched the above protocol well. Notably, the strainer platform was successfully used to label viral proteins, laying the foundation for its application in the visualization of viral infection models. In summary, the potential of the strainer platform for organoid technology was explored further. More extensive exploration of this platform will contribute to the development of organoid technology.

Stability and optimal control of a cytokine-enhanced general HIV infection model with antibody immune response and CTLs immune response

In this article, a cytokine-enhanced viral infection model with cytotoxic T lymphocytes (CTLs) immune response and antibody immune response is proposed and analyzed. The model contains six compartments: uninfected CD4+T cells, infected CD4+T cells, inflammatory cytokines, viruses, CTLs and antibodies. Different from the previous works, this model not only considers virus-to-cell transmission and cell-to-cell transmission, but also includes a new infection mode, namely cytokine-enhanced viral infection. The incidence rates of the healthy CD4+T cells with viruses, infected cells and inflammatory cytokines are given by general functions. Moreover, the production/proliferation and removal/death rates of all compartments are represented by general functions. Firstly, we prove that all the solutions of the model are nonnegative and uniformly bounded. Then, five key parameters with strong biological significance, namely the virus basic reproduction number R 0, CTLs immune response reproduction number R 1, antibody immune response reproductive number R 2, CTLs immune competitive reproductive number R 3 and antibody immune competitive reproductive number R 4 are derived. Then, by using Lyapunov’s method and LaSalle’s invariance principle, we have shown the global stability of each equilibrium. In addition, the numerical simulation results also show that the theoretical results are correct. Finally, we formulate an optimal control problem and solve it using Pontryagins Maximum Principle and an efficient iterative numerical methods. The results of our numerical simulation show that it is very important to control the infection between viruses and cells and between cells and inflammatory cytokines for controlling HIV.

Fractional perspective evaluation of chikungunya infection with saturated incidence functions

It is significant to investigate the transmission dynamics of vector-borne infection because it has a global impact, can help predict and prevent future outbreaks, is important for understanding the impact of climate change on public health, can lead to more effective control strategies, and can improve our comprehension of the dynamics of these infections. Our paper presents a new model for chikungunya virus infection, which considers treatment and vaccination, using the Atangana-Baleanu derivative within the framework of the Caputo definition. First of all, we examine the positivity and uniqueness of the solution for the model. Then, we find out the fundamental results of the suggested model, such as the steady-state without infection and the R0 value that indicates endemicity pertaining to the system. Furthermore, we verify the local asymptotic stability of the infection-free steady-state. Through the application of fixed-point theory, we demonstrate the existence of the solution and propose a numerical methodology to investigate the dynamic behavior of the model. Finally, we performed simulations to demonstrate the effects of vaccination, transmission probability, treatment, and index of memory on the system's solution pathways. The findings of this research suggest the most sensitive parameters of the system responsible for the control and prevention of the infection. Emphasizing the significance of the memory index as an attractive parameter, we propose its consideration to the policy makers as a control parameter for the prevention of the infection.

Fractional order PD control of the Hopf bifurcation of HBV viral systems with multiple time delays

This paper will explore a fractional-order hepatitis B virus (HBV) infection model that takes into account cell-cell and virus-cell transmission and multiple treatment modalities. The desired control strategy is realized by means of a fractional order PD controller. Firstly, we calculated the basic regeneration number and equilibrium point of the HBV model. Afterwards, for the uncontrolled HBV virus system, the adequate conditions for both stability and Hopf bifurcation are systematically investigated via choosing the appropriate time delay as a parameter for bifurcation. Subsequently, under fractional order PD controller, the effect of a proposed controller on system stability and Hopf bifurcation is studied. The desired dynamic characteristics can be obtained afterwards. Finally, numerical simulations show that all three treatments significantly reduce R0. The onset of oscillations can be delayed by decreasing the order of the fractional order. There are three control pathways for fractional order PD control, and the generation of bifurcation can also be delayed by changing the gain parameter. Using the above methods, the diffusion of HBV virus particles in the body can be effectively controlled. The conclusions drawn in this paper are extremely novel and have potential theoretical value for the future treatment of hepatitis B illness.

A Numerical Application of the Chebyshev Operational Matrix Method for HIV Infection of CD4+T-cells

In this research study, we aim to approximate a solution for the mathematical model of the Human Immunodeficiency Virus (HIV) infection of CD4+T-cells. An operational matrix method based on Chebyshev orthogonal polynomials has been adapted to obtain numerical solutions for the model of HIV infection of CD4+T-cells. The proposed numerical scheme is built on a system of a nonlinear algebraic equation, including coefficients of a finite Chebyshev series that are represented the approximate solutions of the model. Results are compared to existing methods to verify the accuracy of the numerical scheme.

Human skin organoids are valid models of mpox virus infection.

Human skin organoids are valid models of mpox virus infection.

A novel investigation of the hepatitis B virus using a fractional operator with a non-local kernel

In order to understand and manage infectious illnesses, mathematical models are extremely important. They support decision making by researchers and public health workers in predicting the spread of diseases, evaluate the results of interventions, and gathering data. This study considers a fractionalized hepatitis B virus (HBV) infection model with cell cure. The Atangana Baleanu fractional model was initially established for the epidemic issue. This paper analyses the fractional form that makes up the HBV infection model utilizing the numerical methodology, homotopy analysis transform method (HATM). The suggested technique is created with the use of the homotopy analysis method (HAM), the homotopy polynomial, and the Laplace transformation. Additionally, the existence and uniqueness of the solution are considered, and stability analysis is given by the fixed-point theory (FPT) of the HBV model. Through MATLAB21, the obtained solutions are graphically simulated. The graphical solutions demonstrated that the peak of viral propagation is reduced when a fractional-order derivative is included to the model, and cell damage is minimized by starting treatment early on; however, the disease takes longer to be completely eradicated. The outcomes will be beneficial in the medical field. The fractional model lets us draw significant information essential for predicting disease outcomes and planning appropriate clinical management for patients.

An analytical approach of applying the Lyapunov direct method to polynomial differential systems with discrete time delays

The Lyapunov direct method is a common and effective tool for discussing the global stability of dynamical systems. In this paper, we propose an analytical approach to apply this method for the global stability of the positive equilibrium of a polynomial differential system with discrete time delays, which includes how to construct an applicable Lyapunov functional and to verify the negative (semi-)definiteness of its derivative. Here the linear combination of the Volterra-type functions/functionals and their integrals plays an important role. Moreover, when the delayed system also has a boundary equilibrium, we show that the Lyapunov functional for the global stability of the positive equilibrium can be reformulated to establish the global stability of the boundary equilibrium. As an illustration, we apply this approach to a virus infection model with two delays.

Ectopic expression of murine CD163 enables cell-culture isolation of lactate dehydrogenase-elevating virus 63 years after its discovery.

Mouse models of viral infection play an especially large role in virology. In 1960, a mouse virus, lactate dehydrogenase-elevating virus (LDV), was discovered and found to have the peculiar ability to evade clearance by the immune system, enabling it to persistently infect an individual mouse for its entire lifespan without causing overt disease. However, researchers were unable to grow LDV in culture, ultimately resulting in the demise of this system as a model of failed immunity. We solve this problem by identifying the cell-surface molecule CD163 as the critical missing component in cell-culture systems, enabling the growth of LDV in immortalized cell lines for the first time. This advance creates abundant opportunities for further characterizing LDV in order to study both failed immunity and the family of viruses to which LDV belongs, Arteriviridae (aka, arteriviruses).

Dynamical analysis of a degenerate and time delayed virus infection model with spatial heterogeneity

AbstractThis paper is concerned with a degenerate and time delayed virus infection model with spatial heterogeneity and general incidence. The well‐posedness of the system, including global existence, uniqueness, and ultimately boundedness of the solutions, as well as the existence of a global attractor, is discussed. The basic reproduction number is defined and a characterization of is presented. Without the compactness of the solution semiflow, we establish the global dynamics of the system based on . In addition, when the system is spatially homogeneous, the unique infection steady state is globally asymptotically stable. Simulations are presented to illustrate our theoretical results.

Partially Hydrolyzed Guar Gum Intake Supports the Gut Microbiota and Attenuates Inflammation during Influenza H1N1 Virus Infection in Mice.

Partially hydrolyzed guar gum (PHGG) is a soluble dietary fiber that is effective for defecation control. It influences the gut microbiota, by which it is metabolized to yield short-chain fatty acids (SCFAs), and it was also recently shown to protect against influenza infection in humans. We here investigated the effects of PHGG in a mouse model of influenza H1N1 virus infection. Eight-week-old C57BL/6 mice were fed normal chow with or without PHGG (500 mg/kg per day) for 4 weeks, infected with H1N1 at 10 weeks of age, and analyzed at 12 weeks of age. Administration of PHGG attenuated the decline in body weight induced by H1N1 infection without affecting food intake. It also ameliorated intestinal atrophy and increased the production of SCFAs including acetic acid, propionic acid, and butyric acid in the cecum, thereby preventing the inhibitory effect of H1N1 infection on SCFA production. The H1N1-induced increases in the serum concentrations of inflammatory cytokines including interferon-γ and interleukin-6 and anti-inflammatory cytokine such as interleukin-10 were all inhibited by PHGG intake. In addition, PHGG administration attenuated inflammatory gene expression in the lung and promoted both natural killer cell activity and regulatory T-cell differentiation in the spleen. Our findings suggest that the consumption of PHGG may improve the gut environment and thereby limit the inflammatory response to H1N1 infection. They may thus provide the basis for novel dietary intervention strategies to suppress the excessive inflammation associated with virus infection.

SARS-COV-2 protein NSP9 promotes cytokine production by targeting TBK1.

SARS-COV-2 infection-induced excessive or uncontrolled cytokine storm may cause injury of host tissue or even death. However, the mechanism by which SARS-COV-2 causes the cytokine storm is unknown. Here, we demonstrated that SARS-COV-2 protein NSP9 promoted cytokine production by interacting with and activating TANK-binding kinase-1 (TBK1). With an rVSV-NSP9 virus infection model, we discovered that an NSP9-induced cytokine storm exacerbated tissue damage and death in mice. Mechanistically, NSP9 promoted the K63-linked ubiquitination and phosphorylation of TBK1, which induced the activation and translocation of IRF3, thereby increasing downstream cytokine production. Moreover, the E3 ubiquitin ligase Midline 1 (MID1) facilitated the K48-linked ubiquitination and degradation of NSP9, whereas virus infection inhibited the interaction between MID1 and NSP9, thereby inhibiting NSP9 degradation. Additionally, we identified Lys59 of NSP9 as a critical ubiquitin site involved in the degradation. These findings elucidate a previously unknown mechanism by which a SARS-COV-2 protein promotes cytokine storm and identifies a novel target for COVID-19 treatment.

A Mouse Model of MHV-1 Virus Infection for Study of Acute and Long COVID Infection.

COVID-19, caused by SARS-CoV-2, has had a significant global impact. While vaccines and treatments have reduced severe cases and deaths, the long-term effects are not yet well understood. Current models used for research, such as non-human primates and transgenic mice, are expensive and require scarce Biosafety Level-3 (BSL-3) laboratories, thereby limiting their practicality. However, the mouse hepatitis virus 1 (MHV-1) mouse model offers a promising alternative. This surrogate model can be investigated in more widely available Biosafety Level-2 (BSL-2) laboratories. Furthermore, mice are affordable and easy to handle, and utilizing MHV-1 as a surrogate for SARS-CoV-2 eliminates the need for costly transgenic mice. Importantly, the MHV-1 model successfully recapitulates COVID-19-related clinical symptoms, weight loss, multiorgan pathological changes and failure in acute stages, irreversible neurological complications, and other long-term organ dysfunction post-infection, which are similar to available human data post-COVID-19. To assist researchers in establishing and using the MHV-1 mouse model, this protocol offers comprehensive guidance encompassing procedures for animal preparation, induction of viral infection, clinical observation, pathological changes, and tissue analysis for mechanistic studies, thereby yielding valuable insights into disease mechanisms and progression. By adopting the MHV-1 model and the provided protocols, researchers can effectively circumvent financial constraints and the limited availability of BSL-3 laboratories, thus facilitating a more accessible and cost-effective approach to investigating the underlying mechanisms of SARS-CoV-2 pathophysiology and exploring potential therapeutic interventions. © 2023 Wiley Periodicals LLC. Basic Protocol: Induction of mouse hepatitis virus 1 (MHV-1) infection in A/J mice Support Protocol 1: Histological evaluation Support Protocol 2: Liver enzyme measurement Support Protocol 3: Western blot analysis of aquaporin expression Support Protocol 4: mRNA measurement Support Protocol 5: Immunohistochemistry/immunofluorescence Support Protocol 6: Tissue water measurement.