Biology subjects

Gulbudak, H.

Publications and source records attributed to Gulbudak, H..

7 recordsLinked to original sources

bioRxiv2024

Eco-evolutionary dynamics of anthelmintic resistance in soil-transmitted helminths

Anthelmintic resistance (AR) of helminth parasites against the most widely available drugs is an ongoing concern for both human and livestock-infecting species. Indeed, there has been substantial evidence of AR in livestock but less in humans, which may be due to a variety of reasons. In this paper, we develop an eco-evolutionary model that couples the life cycle of these parasites with their underlying evolution in a single biallelic genetic locus that confers resistance to treatment drugs. We determine the critical treatment frequency needed to effectively eliminate the population, for a fixed drug efficacy (without evolution) and use this to classify three qualitative distinct behaviors of the eco-evolutionary model. Then, we describe how aspects of the life cycle influence which qualitative outcome is achieved and the spread of the resistance allele, comparing across parameterized models of human- and livestock-infecting species. For all but one species, we find that lower fecundity rates and lower contact rates speed the spread of resistance, while lower larval death slows it down. The life cycle parameters of Ancylostoma duodenale and Ostertagia circumcincta are associated with the fastest and slowest spread of resistance, respectively. We discuss the mechanistic reason for these results.

ecology↗

bioRxiv2023

An Immuno-Epidemiological Model of Foot-and-Mouth Disease (FMD) in the African Buffalo Population with Carrier Transmission

Foot-and-mouth disease (FMD) is a highly contagious disease that spreads among cloven-hoofed animals. Although not deadly, FMD can cause major delays in meat and dairy production. One major concern is that the foot-and-mouth disease virus (FMDV) can persist in African buffalo hosts as natural reservoirs for long periods of time, causing the pathogens to reemerge in susceptible populations. In this paper, we present a novel immuno-epidemiological model of FMD in the African buffalo host populations. Upon infection, the hosts can undergo two phases, namely the acute and the carrier stages. In our model, we divide the infectious population based upon these two stages so that we can dynamically capture the immunological characteristics of both phases of the disease to better understand the carriers role in disease transmission. We first define the within-host viral-immune kinetics dependent epidemiological basic reproduction number[R] 0 and show that it is a threshold condition for the local stability of the disease-free equilibrium and existence of the endemic equilibrium. We also analytically show that the system always displays forward bifurcation with respect to between-host epidemic parameters. Later, by using a sensitivity analysis (SA) approach developed for multi-scale models, we assess the impact of the acute infection and carrier phase immunological parameters on[R] 0. Interestingly, our numerical results show that the within-carrier infected host immune kinetics parameters and the susceptible individual recruitment rates play significant roles in disease persistence, which are consistent with experimental and field studies.

systems biology↗

bioRxiv2023

Robust parameterization of a viral-immune kinetics model for sequential Dengue virus (DENV) infections with Antibody-Dependent Enhancement (ADE)

1Dengue (DENV), a neglected tropical disease, is a globally distributed arboviral (genus Flavivirus) pathogen primarily spread by Aedes mosquitoes and infecting approximately 390 million individuals annually. A challenge to successful control of DENV is that after primary infection (or vaccination) due to waning, secondarily infected patients (or vaccinated individuals) can have an elevated risk of severe Dengue due to a phenomenon known as antibody-dependent enhancement (ADE), that is: preexisting cross-reactive IgG antibody concentrations can increase dengue severity. In this study, we first robustly parameterize a unified within-host viral and immune kinetics model to viral kinetics data for serotypes DENV1, 2, and 3 collected at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam) while allowing independent variation in infection start time among hosts. Our model recapitulates the data well, including cross-reactive antibody concentration-dependent enhanced severity in secondary infections, and captures empirically observed differences between primary and secondary DENV infections, such as time to peak viral load, duration of viremia, and maximum viral titer. Our parameterization also captures meaningful differences in serotype-specific kinetic parameters that drive these differences. Subsequently, we (i) show that variation in initial IgG antibody concentration is sufficient to mechanistically explain the observed differences between primary and secondary infection in terms of the time course of events across serotypes and (ii) leverage our modeling results paired with long-term NS1-specific IgG antibody decay data from Recife, Northeast Brazil, to estimate the half-life of Dengue IgG antibodies and the time frame of the risk window for escalated disease severity due to ADE.

immunology↗

bioRxiv2022

Consilience in disease ecology: FMDV transmission dynamics reflect viral growth and immune response rates.

Infectious disease dynamics operate across biological scales: pathogens replicate within hosts but transmit among populations. Functional changes in the pathogen-host interaction thus generate cascading effects across organizational scales. We investigated within-host dynamics and among-host transmission of three strains (SAT-1, 2, 3) of foot-and-mouth disease viruses (FMDVs) in their wildlife host, African buffalo. We combined data on viral dynamics and host immune responses with mathematical models to ask (i) How do viral and immune dynamics vary among strains?; (ii) Which viral and immune parameters determine viral fitness within hosts?; and (iii) How do within-host dynamics relate to virus transmission? Our data reveal contrasting within-host dynamics among viral strains, with SAT-2 eliciting more rapid and effective immune responses than SAT-1 and SAT-3. Within-host viral fitness was overwhelmingly determined by variation among hosts in immune response activation rates but not by variation among individual hosts in viral growth rate. Our analyses investigating across-scale linkages indicate that viral replication rate in the host correlates with transmission rates among buffalo and that adaptive immune activation rate determines the infectious period. These parameters define the viruss relative basic reproductive number ([R]0), suggesting that viral invasion potential may be predictable from within-host dynamics.

ecology↗

bioRxiv2020

Investigating the impact of combination phage and antibiotic therapy: a modeling study

Antimicrobial resistance (AMR) is a serious threat to global health today. The spread of AMR, along with the lack of new drug classes in the antibiotic pipeline, has resulted in a renewed interest in phage therapy, which is the use of bacteriophages to treat pathogenic bacterial infections. This therapy, which was successfully used to treat a variety of infections in the early twentieth century, had been largely dismissed due to the discovery of easy to use antibiotics. However, the continuing emergence of antibiotic resistance has motivated new interest in the use of phage therapy to treat bacterial infections. Though various models have been developed to address the AMR-related issues, there are very few studies that consider the effect of phage-antibiotic combination therapy. Moreover, some of biological details such as the effect of the immune system on phage have been neglected. To address these limitations, we utilized a mathematical model to examine the role of the immune response in concert with phage-antibiotic combination therapy compounded with the effects of the immune system on the phages being used for treatment. We explore the effect of phage-antibiotic combination therapy by adjusting the phage and antibiotics dose or altering the timing. The model results show that it is important to consider the host immune system in the model and that frequency and dose of treatment are important considerations for the effectiveness of treatment. Our study can lead to development of optimal antibiotic use and further reduce the health risks of the human-animal-plant-ecosystem interface caused by AMR.

microbiology↗

bioRxiv2018

Heterogeneous Viral Strategies Promote Coexistence in Virus-Microbe Systems

Viruses of microbes, including bacterial viruses (phage), archaeal viruses, and eukaryotic viruses, can influence the fate of individual microbes and entire populations. Here, we model distinct modes of virus-host interactions and study their impact on the abundance and diversity of both viruses and their microbial hosts. We consider two distinct viral populations infecting the same microbial population via two different strategies: lytic and chronic. A lytic strategy corresponds to viruses that exclusively infect and lyse their hosts to release new virions. A chronic strategy corresponds to viruses that infect hosts and then continually release new viruses via a budding process without cell lysis. The chronic virus can also be passed on to daughter cells during cell division. The long-term association of virus and microbe in the chronic mode drives differences in selective pressures with respect to the lytic mode. We utilize invasion analysis of the corresponding nonlinear differential equation model to study the ecology and evolution of heterogenous viral strategies. We first investigate stability of equilibria, and characterize oscillatory and bistable dynamics in some parameter regions. Then, we derive fitness quantities for both virus types and investigate conditions for competitive exclusion and coexistence. In so doing we find unexpected results, including a regime in which the chronic virus requires the lytic virus for survival and invasion.

ecology↗

bioRxiv2018

Viral Fitness Across a Continuum from Lysis to Latency

The prevailing paradigm in ecological studies of viruses and their microbial hosts is that the reproductive success of viruses depends on the proliferation of the \"predator\", i.e., the virus particle. Yet, viruses are obligate intracellular parasites, and the virus genome - the actual unit of selection - can persist and proliferate from one cell generation to the next without lysis or the production of new virus particles. Here, we propose a theoretical framework to quantify the invasion fitness of viruses using an epidemiological cell-centric metric that focuses on the proliferation of viral genomes inside cells instead of virus particles outside cells. This cell-centric metric enables direct comparison of viral strategies characterized by obligate killing of hosts (e.g., via lysis), persistence of viral genomes inside hosts (e.g., via lysogeny), and strategies along a continuum between these extremes (e.g., via chronic infections). As a result, we can identify environmental drivers, life history traits, and key feedbacks that govern variation in viral propagation in nonlinear population models. For example, we identify threshold conditions given relatively low densities of susceptible cells and relatively high growth rates of infected cells in which lysogenic and other chronic strategies have higher potential viral reproduction than lytic strategies. Altogether, the theoretical framework helps unify the ongoing study of eco-evolutionary drivers of viral strategies in natural environments.

ecology↗