Mathematical modelling identifies the role of adaptive immunity as a key controller of respiratory syncytial virus in cotton rats

Wethington, Darren; Harder, Olivia; Uppulury, Karthik; Stewart, William C.; Chen, Phylip; King, Tiffany; Reynolds, Susan D.; Perelson, Alan S.; Peeples, Mark E.; Niewiesk, Stefan; Das, Jayajit

doi:10.1098/rsif.2019.0389

Cited by 19 publications

(21 citation statements)

References 56 publications

(157 reference statements)

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“…We attempt to determine which of these scenarios is occurring through the use of mathematical models. Mathematical models have long been used to improve our understanding of respiratory viral infections 25 and to study different aspects of within-host dynamics of viral infections, such as drug treatment 26,27 and resistance, [28][29][30] the role of the immune response, 31,32 and coinfections. [33][34][35] Our previous study using mathematical models of coinfections indicated that viruses with a faster growth rate will suppress viruses with a slower growth rate, 33 a dynamic that might provide insight into SARS-CoV-2 coinfections with other respiratory viruses.…”

Section: Introductionmentioning

confidence: 99%

SARS‐CoV‐2 coinfections: Could influenza and the common cold be beneficial?

Pinky

Dobrovolny

2020

Journal of Medical Virology

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The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world, causing serious illness and death and creating a heavy burden on the healthcare systems of many countries. Since the virus first emerged in late November 2019, its spread has coincided with peak circulation of several seasonal respiratory viruses, yet some studies have noted limited coinfections between SARS-CoV-2 and other viruses. We use a mathematical model of viral coinfection to study SARS-CoV-2 coinfections, finding that SARS-CoV-2 replication is easily suppressed by many common respiratory viruses. According to our model, this suppression is because SARS-CoV-2 has a lower growth rate (1.8 /d) than the other viruses examined in this study. The suppression of SARS-CoV-2 by other pathogens could have implications for the timing and severity of a second wave.

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Section: Introductionmentioning

confidence: 99%

SARS‐CoV‐2 coinfections: Could influenza and the common cold be beneficial?

Pinky

Dobrovolny

2020

Journal of Medical Virology

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“…Inbred male and female cotton rats (Sigmodon hispidus) were purchased from Envigo (Indianapolis, Indiana) and housed as previously described [ 32 , 33 ] in polysulfone microisolation cages (NextGen Rat 900, Allentown Inc., Allentown, NJ, USA) in a barrier facility with a 12:12 hour light cycle. Cotton rats were maintained at 20 ± 2°C and 30% to 70% relative humidity.…”

Section: Methodsmentioning

confidence: 99%

“…Stocks of RSV A2 were grown in human epithelial (HEp2) cells as described [ 32 , 33 ]. HEp2 cells were infected with an MOI of 0.001 of RSV A2 in MEM for 1 hour at 37°C and incubated in 30 mL MEM/2% fetal calf serum at 37°C for 4 days.…”

Section: Methodsmentioning

confidence: 99%

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Immunogenicity and inflammatory properties of respiratory syncytial virus attachment G protein in cotton rats

et al. 2021

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Human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants and young children worldwide. The attachment (G) protein of RSV is synthesized by infected cells in both a membrane bound (mG) and secreted form (sG) and uses a CX3C motif for binding to its cellular receptor. Cell culture and mouse studies suggest that the G protein mimics the cytokine CX3CL1 by binding to CX3CR1 on immune cells, which is thought to cause increased pulmonary inflammation in vivo. However, because these studies have used RSV lacking its G protein gene or blockade of the G protein with a G protein specific monoclonal antibody, the observed reduction in inflammation may be due to reduced virus replication and spread, and not to a direct role for G protein as a viral chemokine. In order to more directly determine the influence of the soluble and the membrane-bound forms of G protein on the immune system independent of its attachment function for the virion, we expressed the G protein in cotton rat lungs using adeno-associated virus (AAV), a vector system which does not itself induce inflammation. We found no increase in pulmonary inflammation as determined by histology and bronchoalveolar lavage after inoculation of AAVs expressing the membrane bound G protein, the secreted G protein or the complete G protein gene which expresses both forms. The long-term low-level expression of AAV-G did, however, result in the induction of non-neutralizing antibodies, CD8 T cells and partial protection from challenge with RSV. Complete protection was accomplished through co-immunization with AAV-G and an AAV expressing cotton rat interferon α.

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“…Therefore, we analyzed the differences in airway resistance, tissue damping and pulmonary compliance in RSV infected female and male cotton rats. We compared pulmonary function at 4 days post-RSV infection since this is the time point in which there is peak viral replication in the lungs of cotton rats [46].…”

Section: Female and Not Male Cotton Rats Demonstrated Perturbationsmentioning

confidence: 99%

Pulmonary function analysis in cotton rats after respiratory syncytial virus infection

et al. 2020

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The cotton rat (Sigmodon hispidus) is an excellent small animal model for human respiratory viral infections such as human respiratory syncytial virus (RSV) and human metapneumovirus (HMPV). These respiratory viral infections, as well as other pulmonary inflammatory diseases such as asthma, are associated with lung mechanic disturbances. So far, the pathophysiological effects of viral infection and allergy on cotton rat lungs have not been measured, although this information might be an important tool to determine the efficacy of vaccine and drug candidates. To characterize pulmonary function in the cotton rat, we established forced oscillation technique in uninfected, RSV infected and HDM sensitized cotton rats, and characterized pulmonary inflammation, mucus production, pulmonary edema, and oxygenation. There was a gender difference after RSV infection, with females demonstrating airway hyper-responsiveness while males did not. Female cotton rats 2dpi had a mild increase in pulmonary edema (wet: dry weight ratios). At day 4 post infection, female cotton rats demonstrated mild pulmonary inflammation, no increase in mucus production or reduction in oxygenation. Pulmonary function was not significantly impaired after RSV infection. In contrast, cotton rats sensitized to HDM demonstrated airway hyperresponsiveness with a significant increase in pulmonary inflammation, increase in baseline tissue damping, and a decrease in baseline pulmonary compliance. In summary, we established baseline data for forced oscillation technique and other respiratory measures in the cotton rat and used it to analyze respiratory diseases in cotton rats.

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Mathematical modelling identifies the role of adaptive immunity as a key controller of respiratory syncytial virus in cotton rats

Cited by 19 publications

References 56 publications

SARS‐CoV‐2 coinfections: Could influenza and the common cold be beneficial?

SARS‐CoV‐2 coinfections: Could influenza and the common cold be beneficial?

Immunogenicity and inflammatory properties of respiratory syncytial virus attachment G protein in cotton rats

Pulmonary function analysis in cotton rats after respiratory syncytial virus infection

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