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Vitaly V Ganusov

Publications and source records attributed to Vitaly V Ganusov.

14 recordsLinked to original sources
PubMed2026

Immortal genome assumption significantly underestimates replication and death rates of Mycobacterium tuberculosis in mice and monkeys.

Immune correlates of protection against infection with Mycobacterium tuberculosis (Mtb) or against tuberculosis (TB) remain poorly defined. The ratio of colony forming units (CFUs) to chromosomal equivalents (CEQs), Z = CFUs/CEQs, recovered either from the whole lung (mice) or individual lesions (monkeys or rabbits) of Mtb-infected animals has been used as a metric for how effectively Mtb is killed in vivo. However, the contribution of bacterial killing to changes in the CFU/CEQ ratio during an infection has not been rigorously investigated. We developed alternative mathematical models to study the dynamics of CFUs, CEQs, and their ratio during an Mtb infection. We find that the ratioalone cannot be used to infer the death rate of bacteria, unless the dynamics of CEQs and CFUs are entirely uncoupled, which is biologically unreasonable and inconsistent with the view that CEQs reflect an accumulated burden of both viable and non-viable bacteria. Importantly, we estimate a decay rate of 3.6%/day (a half life of about 20 days) of Mtb H37Rv CEQs in B6 mice that is similar to 4%/day, previously found for Mtb Erdman in cynomolgus macaques. While the estimated Mtb DNA decay rate seems small, we found that estimated rates of Mtb replication and death/killing are still extremely sensitive even to slow decay of Mtb DNA, in part, because Mtb replication and death rates are also small especially during chronic phases of infection. By applying our models to data on Mtb dynamics during the first 3 weeks of infection in macaques, we provide evidence of substantial killing of Mtb bacteria, prior to arrival of adaptive immunity to the site of infection, challenging the previously established notion of non-dying bacteria in the absence of T cell immunity and granuloma formation. We also propose experiments that will allow more accurately to measure the rate of Mtb DNA loss, helping more rigorously quantify impact of immunity on within-host Mtb dynamics.

Mycobacterium tuberculosis↗
PubMed2006

How does cross-reactive stimulation affect the longevity of CD8+ T cell memory?

Immunological memory--the ability to "remember" previously encountered pathogens and respond faster upon re-exposure is a central feature of the immune response in vertebrates. The cross-reactive stimulation hypothesis for the maintenance of memory proposes that memory cells specific for a given pathogen are maintained by cross-reactive stimulation following infections with other (unrelated) pathogens. We use mathematical models to examine the cross-reactive stimulation hypothesis. We find that: (i) the direct boosting of cross-reactive lineages only provides a very small increase in the average longevity of immunological memory; (ii) the expansion of cross-reactive lineages can indirectly increase the longevity of memory by reducing the magnitude of expansion of new naive lineages which occupy space in the memory compartment and are responsible for the decline in memory; (iii) cross-reactive stimulation results in variation in the rates of decline of different lineages of memory cells and enrichment of memory cell population for cells that are cross-reactive for the pathogens to which the individual has been exposed.

Animals↗
PubMed2006

Estimating lymphocyte division and death rates from CFSE data.

The division tracking dye, carboxyfluorescin diacetate succinimidyl ester (CFSE) is currently the most informative labeling technique for characterizing the division history of cells in the immune system. Gett and Hodgkin [Nat. Immunol. 1:239-244, 2000] have pioneered the quantitative analysis of CFSE data. We confirm and extend their data analysis approach using simple mathematical models. We employ the extended Gett and Hodgkin [Nat. Immunol. 1:239-244, 2000] method to estimate the time to first division, the fraction of cells recruited into division, the cell cycle time, and the average death rate from CFSE data on T cells stimulated under different concentrations of IL-2. The same data is also fitted with a simple mathematical model that we derived by reformulating the numerical model of Deenick et al. [J. Immunol. 170:4963-4972, 2003]. By a non-linear fitting procedure we estimate parameter values and confidence intervals to identify the parameters that are influenced by the IL-2 concentration. We obtain a significantly better fit to the data when we assume that the T cell death rate depends on the number of divisions cells have completed. We provide an outlook on future work that involves extending the Deenick et al. [J. Immunol. 170:4963-4972, 2003] model into the classical smith-martin model, and into a model with arbitrary probability distributions for death and division through subsequent divisions.

Cell Death↗
PubMed2006

Estimating Costs and Benefits of CTL Escape Mutations in SIV/HIV Infection.

Mutations that allow SIV/HIV to avoid the cytotoxic T lymphocyte (CTL) response are well documented. Recently, there have been a few attempts at estimating the costs of CTL escape mutations in terms of the reduction in viral fitness and the killing rate at which the CTL response specific to one viral epitope clears virus-infected cells. Using a mathematical model we show that estimation of both parameters depends critically on the underlying changes in the replication rate of the virus and the changes in the killing rate over time (which in previous studies were assumed to be constant). We provide a theoretical basis for estimation of these parameters using in vivo data. In particular, we show that 1) by assuming unlimited virus growth one can obtain a minimal estimate of the fitness cost of the escape mutation, and 2) by assuming no virus growth during the escape, one can obtain a minimal estimate of the average killing rate. We also discuss the conditions under which better estimates of the average killing rate can be obtained.

Animals↗
PubMed2006

Imperfect vaccines and the evolution of pathogens causing acute infections in vertebrates.

A study by Gandon et al. (2001) considered the potential ways pathogens may evolve in response to vaccination with imperfect vaccines. In this paper, by focusing on acute infections of vertebrate hosts, we examine whether imperfect vaccines that do not completely block a pathogen's replication (antigrowth) or transmission (antitransmission) may lead to evolution of more or less virulent pathogen strains. To address this question, we use models of the within-host dynamics of the pathogen and the host's immune responses. One advantage of the use of this within-host approach is that vaccination can be easily incorporated in the models and the trade-offs between pathogen transmissibility, host recovery, and virulence that drive evolution of pathogens in these models can be easily estimated. We find that the use of either antigrowth or antitransmission vaccines leads to the evolution of pathogens with an increased within-host growth rate; infection of unvaccinated hosts with such evolved pathogens results in high host mortality and low pathogen transmission. Vaccination of only a fraction of hosts with antigrowth vaccines may prevent pathogens from evolving high virulence due to pathogen adaptation to unvaccinated hosts and thus protection of vaccinated hosts from pathogen-induced disease. In contrast, antitransmission vaccines may be beneficial only if they are effective enough to cause pathogen extinction. Our results suggest that particular mechanisms of action of vaccines and their efficacy are crucial in predicting longterm evolutionary consequences of the use of imperfect vaccines.

Animal Diseases↗
PubMed2005

Pathology during acute infections: contributions of intracellular pathogens and the CTL response.

Previous work has shown how, in the case of cytotoxic T-lymphocyte (CTL) responses to persistent viral infections, pathology may arise as a consequence of cell destruction directly by the virus or indirectly due to the CTL response, leading to maximum pathology at intermediate efficacy of the immune response. We expand these studies to consider pathology arising during acute infections with intracellular pathogens controlled by the CTL response. We show that, in contrast to persistent infections, pathology during acute infections is minimized with increasing efficacy of the immune response. The implications of these results for vaccination are discussed.

Humans↗
PubMed2005

Quantifying cell turnover using CFSE data.

The CFSE dye dilution assay is widely used to determine the number of divisions a given CFSE labelled cell has undergone in vitro and in vivo. In this paper, we consider how the data obtained with the use of CFSE (CFSE data) can be used to estimate the parameters determining cell division and death. For a homogeneous cell population (i.e., a population with the parameters for cell division and death being independent of time and the number of divisions cells have undergone), we consider a specific biologically based "Smith-Martin" model of cell turnover and analyze three different techniques for estimation of its parameters: direct fitting, indirect fitting and rescaling method. We find that using only CFSE data, the duration of the division phase (i.e., approximately the S+G2+M phase of the cell cycle) can be estimated with the use of either technique. In some cases, the average division or cell cycle time can be estimated using the direct fitting of the model solution to the data or by using the Gett-Hodgkin method [Gett A. and Hodgkin, P. 2000. A cellular calculus for signal integration by T cells. Nat. Immunol. 1:239-244]. Estimation of the death rates during commitment to division (i.e., approximately the G1 phase of the cell cycle) and during the division phase may not be feasible with the use of only CFSE data. We propose that measuring an additional parameter, the fraction of cells in division, may allow estimation of all model parameters including the death rates during different stages of the cell cycle.

Algorithms↗
PubMed2005

The role of models in understanding CD8+ T-cell memory.

Immunological memory - the ability to 'remember' previously encountered pathogens and respond faster on re-exposure - is a central feature of the immune response of vertebrates. We outline how mathematical models have contributed to our understanding of CD8(+) T-cell memory. Together with experimental data, models have helped to quantitatively describe and to further our understanding of both the generation of memory after infection with a pathogen and the maintenance of this memory throughout the life of an individual.

Animals↗
PubMed2003

The rescaling method for quantifying the turnover of cell populations.

The dynamic nature of immune responses requires the development of appropriate experimental and theoretical tools to quantitatively estimate the division and death rates which determine the turnover of immune cells. A number of papers have used experimental data from BrdU and D-glucose labels together with a simple random birth-death model to quantify the turnover of immune cells focusing on HIV/SIV infections [Mohri et al. 279 (1998) 1223-1227, Hellerstein et al. 5 (1999) 83-89, Bonhoeffer et al. 164 (2000) 5049-5054, Mohri et al. 87 (2001) 1277-1287]. We show how uncertainties in the assumptions of the random birth-death model may lead to substantial errors in the parameters estimated. We then show how more accurate estimates can be obtained from the more recent CFSE data which allow to track the number of divisions each cell has undergone. Specifically, we: (i) describe a general stage-structured model of cell division where the probabilities of division and death are functions of time since the previous division; (ii) develop a rescaling method to identify invariant parameters (i.e. the ones that are independent of the specific functions describing division and death); (iii) show how these invariant parameters can be estimated, and (iv) illustrate this technique by applying it to CFSE data taken from the literature.

Adoptive Transfer↗
PubMed2003

The role of the cytotoxic T-lymphocyte response and virus cytopathogenicity in the virus decline during antiviral therapy.

Although it is clear that HIV can lyse HIV-infected CD4 T cells, it is still controversial whether the depletion of CD4 T cells seen in HIV-infected patients after years of asymptomatic disease is caused by the direct cytopathic effects of the virus or is mediated by the immune response. Assuming the initial decline in viraemia during highly active antiretroviral therapy (HAART) is caused by the death of cells productively infected with HIV, I investigate how the rate of the virus decline is affected by the efficiency of the cytotoxic T-lymphocyte (CTL) response. I find that whether the stronger immune response causes a more rapid virus decline depends critically on how the virus is controlled by the CTL response (lytic versus non-lytic mechanisms). Moreover, variation in the efficiency of the immune response does not always cause variation in the rate of the virus decline (and, therefore, in the death rate of infected cells), implying that the constancy of the virus decline rate measured in different patients does not necessarily indicate that the virus is cytopathic. The potential problems associated with the model and the approach undertaken are also discussed.

Antiretroviral Therapy, Highly Active↗
PubMed2003

Trade-offs and the evolution of virulence of microparasites: do details matter?

Models of the within-host dynamics of parasites have been used to consider the evolution of microparasites causing acute infections in vertebrate hosts. In this paper, we use these models to examine how the level of virulence to which a parasite evolves, depends on factors such as the relationship between parasite density and its rate of transmission from infected hosts, and the mechanism of parasite-induced pathogenesis. We show that changes in the terms describing transmissibility and pathogenesis may lead to dramatic differences in the level of virulence to which a parasite evolves. This suggests that no single factor is likely to be responsible for the differences in virulence of different parasites, and that understanding of the evolution of virulence of parasites will require a detailed quantitative understanding of the interaction between the parasite and its host.

Adaptation, Biological↗
PubMed2002

Estimating the instability parameters of plasmid-bearing cells. I. Chemostat culture.

What determines the stability of plasmid-bearing cells in natural and laboratory conditions? In order to answer this question in a quantitative manner, we need tools allowing the estimation of parameters governing plasmid loss in different environments. In the present work, we have developed two methods for the estimation of the instability parameters of plasmid-bearing cells growing in chemostat. These instability parameters are: (i) selection coefficient (or cost of the plasmid)alpha and (ii) the probability of plasmid loss at cell division tau(0). We have found that generally selection coefficient alpha changes during elimination of plasmid-bearing cells due to changes in substrate concentration; hence, methods which assume constancy of alpha are intrinsically imprecise. Instead, one can estimate selection coefficient at the beginning and the end of cultivation when the substrate concentration is approximately constant. Applying developed techniques to two sets of experimental data, we have found that (i) the cost of the plasmid pBR322 depended on the dilution rate in chemostat and was higher at low dilutions; (ii) high levels of plasmid gene expression led to a high cost of the plasmid pPHL-7; (iii) the probability of plasmid loss was lower at high levels of plasmid gene expression and independent of the dilution rate. We have also discussed the application of our results to understanding the basic biology of bacterial plasmids.

Animals↗
PubMed2002

Within-host population dynamics and the evolution of microparasites in a heterogeneous host population.

Why do parasites harm their hosts? The general understanding is that if the transmission rate and virulence of a parasite are linked, then the parasite must harm its host to maximize its transmission. The exact nature of such trade-offs remains largely unclear, but for vertebrate hosts it probably involves interactions between a microparasite and the host immune system. Previous results have suggested that in a homogeneous host population in the absence of super- or coinfection, within-host dynamics lead to selection of the parasite with an intermediate growth rate that is just being controlled by the immune system before it kills the host (Antia et al. 1994). In this paper, we examine how this result changes when heterogeneity is introduced to the host population. We incorporate the simplest form of heterogeneity--random heterogeneity in the parameters describing the size of the initial parasite inoculum, the immune response of the host, and the lethal density at which the parasite kills the host. We find that the general conclusion of the previous model holds: parasites evolve some intermediate growth rate. However, in contrast with the generally accepted view, we find that virulence (measured by the case mortality or the rate of parasite-induced host mortality) increases with heterogeneity. Finally, we link the within-host and between-host dynamics of parasites. We show how the parameters for epidemiological spread of the disease can be estimated from the within-host dynamics, and in doing so examine the way in which trade-offs between these epidemiological parameters arise as a consequence of the interaction of the parasite and the immune response of the host.

Animals↗