ANTIVIRAL AND ANTI-HIV EFFECT OF PHYTOCONSTIUENTS OBTAINED FROM LEAVES EXTRACT OF DENOLIX REGIA TREE ON RATS MODEL

 Denolix Regia.

Common name: Flame Tree, Royal Poinciana • Hindi: Gulmohar गुलमोहर • Bengali: Krishnachura • Kannada: Kempu torai • Kannada: ಕೆಂಪುತುರಾಯಿ Kempu turai, ಕತ್ತಿಕಾಯಿಮರ Kattikaayi mara, ಸೀಮೆಸಂಕೇಶ್ವರ Seeme sankeshwara • Mizo: April-par

Botanical name: Delonix regia    Family: Caesalpiniaceae (Gulmohar family)

Traditionally Delonix regia (Boj.) Raf. has been used in various ailments such as chronic fever, antimicrobial, constipation, inflammation, arthritis, hemoplagia, piles, boils, pyorrhea, scorpion bite, bronchitis, asthma and dysmenorrhoea.

We present an immune system simulator based on a

hybrid discrete/continuous approach. In particular, sim-

ulated lymphocytes, antigens and immunocomplexes are

treated as stochastic discrete entities whereas interleukins,

chemokines and in general small signalling molecules are

described as continuous variables ruled by differential

equations.

The version of the model we present here is customized

to reproduce the immune response to HIV and the effects

of an anti-retroviral therapy. Our goal is to suggest new

therapeutic strategies that can be tested in a computer.

Mouse models

The main impediment to the infection of mouse (Mus musculus) cells with SARS-CoV-2 is the lack of appropriate receptors to initiate viral infection. SARS-CoV-2—as severe acute respiratory syndrome coronavirus (SARS-CoV)—uses the cellular surface protein angiotensin-converting enzyme 2 (ACE2) to bind and enter cells, and mouse ACE2 does not effectively bind the viral spike protein7. Several strategies have been developed to solve this problem, as detailed here.

Virus adaptation to mouse ACE2

The spike protein of SARS-CoV-2 can be modified to gain effective binding to mouse ACE2. One strategy to achieve this modification is the sequential passaging of SARS-CoV-2 in mouse lung tissue8. This method is successful because populations of RNA viruses consist of a swarm of closely related viral quasispecies. Rare viruses in the swarm that contain mutations in the spike protein that increase their binding affinity to mouse ACE2 are expected to be selected, owing to their higher levels of replication in mouse lungs. Alternatively, SARS-CoV-2 can be adapted to infect mouse cells by using reverse genetics to modify the receptor-binding domain of the virus so that it can infect mouse cells via the mouse ACE2 protein. Using two approaches, mice have been sensitized for infection but have developed only very mild disease9. It is likely that additional efforts aimed at adapting SARS-CoV-2 to mice will result in the outgrowth of additional virus variants that can cause more severe disease. These mice will then be useful for pathogenesis studies, and for studies of antiviral agents and vaccines. One potential caveat is that the mutations in the SARS-CoV-2 spike protein that enhance affinity for the mouse ACE2 receptors are located in the receptor-binding domain, which is the primary target for the neutralizing antibody response. These mutations could thus result in a monoclonal antibody that neutralizes the wild-type virus being falsely considered as non-neutralizing.

 

Mouse models

The main impediment to the infection of mouse (Mus musculus) cells with SARS-CoV-2 is the lack of appropriate receptors to initiate viral infection. SARS-CoV-2—as severe acute respiratory syndrome coronavirus (SARS-CoV)—uses the cellular surface protein angiotensin-converting enzyme 2 (ACE2) to bind and enter cells, and mouse ACE2 does not effectively bind the viral spike protein. Several strategies have been developed to solve this problem, as detailed here.

Virus adaptation to mouse ACE2

The spike protein of SARS-CoV-2 can be modified to gain effective binding to mouse ACE2. One strategy to achieve this modification is the sequential passaging of SARS-CoV-2 in mouse lung tissue. This method is successful because populations of RNA viruses consist of a swarm of closely related viral quasispecies. Rare viruses in the swarm that contain mutations in the spike protein that increase their binding affinity to mouse ACE2 are expected to be selected, owing to their higher levels of replication in mouse lungs. Alternatively, SARS-CoV-2 can be adapted to infect mouse cells by using reverse genetics to modify the receptor-binding domain of the virus so that it can infect mouse cells via the mouse ACE2 protein. Using two approaches, mice have been sensitized for infection but have developed only very mild disease. It is likely that additional efforts aimed at adapting SARS-CoV-2 to mice will result in the outgrowth of additional virus variants that can cause more severe disease. These mice will then be useful for pathogenesis studies, and for studies of antiviral agents and vaccines. One potential caveat is that the mutations in the SARS-CoV-2 spike protein that enhance affinity for the mouse ACE2 receptors are located in the receptor-binding domain, which is the primary target for the neutralizing antibody response. These mutations could thus result in a monoclonal antibody that neutralizes the wild-type virus being falsely considered as non-neutralizing.

Expression of human ACE2 in genetically modified mice

Another approach to infect mice with SARS-CoV-2 consists of modifying the mice to express human ACE2. There are currently three transgenic mouse models, in which human ACE2 is under the expression of a tissue-specific promoter (for example, the Krt18 promoter for epithelial cells; K18-hACE2 mice), a universal promoter (cytomegalovirus enhancer followed by the chicken β-actin promoter) or the endogenous mouse Ace2 promoter. All of these mice are susceptible to infection by SARS-CoV-2, but differences in their expression of human ACE2 result in a pathogenic range of mild to lethal disease. With the exception of the model in which human ACE2 is controlled by the Ace2 promoter, mice develop encephalitis after infection with SARS-CoV1 or SARS-CoV-2 in these models. However, while SARS-CoV infection of K18-hACE2 mice results in highly lethal encephalitis, the neurological infection caused by SARS-CoV-2 infection in these mice is less severe. Some mice appear to succumb to severe pneumonia, at times at which the brain infection is not substantial. Notably, these mice develop evidence of thrombosis and anosmia after infection with SARS-CoV-2 and have been used for studies of the innate and T cell responses. Mice develop severe disease after infection with SARS-CoV-2 in these models, and therefore may provide proof-of-concept data to support vaccine and therapeutic efficacy and may be useful for pathogenesis studies.

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Syrian hamster model

Syrian hamsters (Mesocricetus auratus) are small mammals that have been used as models for infection with respiratory viruses, including SARS-CoV, influenza virus and adenovirus. In silico comparison of the ACE2 sequence of humans—known to interact with the receptor-binding domain of the SARS-CoV-2 spike glycoprotein—with that of hamsters.  suggested that Syrian hamsters might be susceptible to infection with SARS-CoV-2. Upon experimental intranasal infection, Syrian hamsters show mild-to-moderate disease with progressive weight loss that starts very early after infection (days 1–2 after inoculation). All hamsters that have been challenged by different groups and with different SARS-CoV-2 isolates consistently showed signs of respiratory distress, including laboured breathing. Additional signs of morbidity included lethargy, ruffled fur and a hunched posture. After two weeks of infection, hamsters typically recovered. Of particular interest is the fact that infection with SARS-CoV-2 in hamsters reflects some of the demographic differences of COVID-19 in humans. Thus, aged hamsters and male hamsters seem to develop a more severe disease than young and female hamsters, respectively

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