Life cycle process dependencies of positive-sense RNA viruses suggest strategies for inhibiting productive cellular infection

Chhajer, Harsh; Rizvi, Vaseef A.; Roy, Rahul

doi:10.1098/rsif.2021.0401

Cited by 7 publications

(8 citation statements)

References 86 publications

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“…The initial percentage of EdU‐tagged cells, α in the proliferation pool, is a parameter in the model. The distribution of parameters yielding acceptable agreement between model and data is obtained using iterative approximate Bayesian computation (iABC) 19 and iABC procedure was implemented as described 20 . For distributions resulting from genetic algorithm (GA), GA in global optimization toolbox of MATLAB R2020b is used.…”

Section: Methodsmentioning

confidence: 99%

Sterile inflammation alters neutrophil kinetics in mice

Alakesh

Jothiprakasam

Raghavan

et al. 2022

Journal of Leukocyte Biology

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Neutrophils play a crucial role in establishing inflammation in response to an infection or injury, but their production rates, as well as blood and tissue residence times, remain poorly characterized under these conditions. Herein, using a biomaterial implant model to establish inflammation followed by in vivo tracking of newly formed neutrophils, we determine neutrophil kinetics under inflammatory conditions. To obtain quantifiable information from our experimental observations, we develop an ordinary differential equation‐based mathematical model to extract kinetic parameters. Our data show that in the presence of inflammation resulting in emergency granulopoiesis‐like conditions, neutrophil maturation time in the bone marrow reduces by around 60% and reduced half‐life in the blood, compared with noninflammatory conditions. Additionally, neutrophil residence time at the inflammatory site increases by 2‐fold. Together, these data improve our understanding of neutrophil kinetics under inflammatory conditions, which could pave the way for therapies that focus on modulating in vivo neutrophil dynamics.

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Section: Methodsmentioning

confidence: 99%

Sterile inflammation alters neutrophil kinetics in mice

Alakesh

Jothiprakasam

Raghavan

et al. 2022

Journal of Leukocyte Biology

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“…The upregulation of ISG15 and ISG20 fit in with the known upregulation of a host of ISGs as part of the innate immune response to a viral infection (72, 73). Additional functional enrichments reflecting different WGCNA modules have previously been described anti-apoptosis (74), heat shock response (75, 76), unfolded protein response (77), translation (78), IgM (79), cell adhesion and pathogen attachment (80), endothelial activation (81) and macrophage activation (82, 83). In comparison to other neurological infections, there was a downregulation in acute phase response proteins and neutrophil enriched proteins, as has been seen by other studies (84–87).…”

Section: Discussionmentioning

confidence: 92%

Deep proteomics network and machine learning analysis of human cerebrospinal fluid in Japanese encephalitis virus infection

Bharucha

Gangadharan

Kumar

et al. 2022

Preprint

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Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus, and leading cause of neurological infection in Asia and the Pacific, with recent emergence in multiple territories in Australia in 2022. Patients may experience devastating socioeconomic consequences; JEV infection (JE) predominantly affects children in poor rural areas, has a 20-30% case fatality rate, and 30-50% of survivors suffer long-term disability. JEV RNA is rarely detected in patient samples, and the standard diagnostic test is an anti-JEV IgM ELISA with sub-optimal specificity; there is no means of detection in more remote areas. We aimed to test the hypothesis that there is a diagnostic protein signature of JE in human cerebrospinal fluid (CSF), and contribute to understanding of the host response and predictors of outcome during infection. We retrospectively tested a cohort of 163 patients recruited as part of the Laos central nervous system infection study. Application of liquid chromatography and tandem mass spectrometry (LC-MS/MS), using extensive offline fractionation and tandem mass tag labelling, enabled a comparison of the CSF proteome in 68 JE patient vs 95 non-JE neurological infections. 5,070 proteins were identified, including 4,805 human proteins and 265 pathogen proteins. We incorporated univariate analysis of differential protein expression, network analysis and machine learning techniques to build a ten-protein diagnostic signature of JE with >99% diagnostic accuracy. Pathways related to JE infection included neuronal damage, anti-apoptosis, heat shock and unfolded protein responses, cell adhesion, macrophage and dendritic cell activation as well as a reduced acute inflammatory response, hepatotoxicity, activation of coagulation, extracellular matrix and actin regulation. We verified the results by performing DIA LC-MS/MS in 16 (10%) of the samples, demonstrating 87% accuracy using the same model. Ultimately, antibody-based validation will be required, in a larger group of patients, in different locations and in field settings, to refine the list to 2-3 proteins that could be harnessed in a rapid diagnostic test.

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“…Furthermore, those virus-specific models are usually developed to study a particular aspect of the viral life cycle, such as cell-line-specific HCV RNA replication efficiency [19] or the life cycles of DENV or CVB3 in the presence of the immune response [55,81]. Recently, Chhajer et al (2021) studied the viral life cycles of the plus-strand RNA viruses HCV, Japanese encephalitis virus, and poliovirus with a simplified mathematical model. The authors mainly focused on the slow and delayed kinetics of the intracellular formation of replication organelles, which may predict infection outcomes [89].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Chhajer et al (2021) studied the viral life cycles of the plus-strand RNA viruses HCV, Japanese encephalitis virus, and poliovirus with a simplified mathematical model. The authors mainly focused on the slow and delayed kinetics of the intracellular formation of replication organelles, which may predict infection outcomes [89].…”

Section: Discussionmentioning

confidence: 99%

Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies

et al. 2023

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Plus-strand RNA viruses are the largest group of viruses. Many are human pathogens that inflict a socio-economic burden. Interestingly, plus-strand RNA viruses share remarkable similarities in their replication. A hallmark of plus-strand RNA viruses is the remodeling of intracellular membranes to establish replication organelles (so-called “replication factories”), which provide a protected environment for the replicase complex, consisting of the viral genome and proteins necessary for viral RNA synthesis. In the current study, we investigate pan-viral similarities and virus-specific differences in the life cycle of this highly relevant group of viruses. We first measured the kinetics of viral RNA, viral protein, and infectious virus particle production of hepatitis C virus (HCV), dengue virus (DENV), and coxsackievirus B3 (CVB3) in the immuno-compromised Huh7 cell line and thus without perturbations by an intrinsic immune response. Based on these measurements, we developed a detailed mathematical model of the replication of HCV, DENV, and CVB3 and showed that only small virus-specific changes in the model were necessary to describe the in vitro dynamics of the different viruses. Our model correctly predicted virus-specific mechanisms such as host cell translation shut off and different kinetics of replication organelles. Further, our model suggests that the ability to suppress or shut down host cell mRNA translation may be a key factor for in vitro replication efficiency, which may determine acute self-limited or chronic infection. We further analyzed potential broad-spectrum antiviral treatment options in silico and found that targeting viral RNA translation, such as polyprotein cleavage and viral RNA synthesis, may be the most promising drug targets for all plus-strand RNA viruses. Moreover, we found that targeting only the formation of replicase complexes did not stop the in vitro viral replication early in infection, while inhibiting intracellular trafficking processes may even lead to amplified viral growth.

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Life cycle process dependencies of positive-sense RNA viruses suggest strategies for inhibiting productive cellular infection

Cited by 7 publications

References 86 publications

Sterile inflammation alters neutrophil kinetics in mice

Sterile inflammation alters neutrophil kinetics in mice

Deep proteomics network and machine learning analysis of human cerebrospinal fluid in Japanese encephalitis virus infection

Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies

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