Mathematical Problems in Engineering

Mathematical Problems in Engineering / 2021 / Article

Research Article | Open Access

Volume 2021 |Article ID 8879538 |

S. P. Rajasekar, M. Pitchaimani, Quanxin Zhu, Kaibo Shi, "Exploring the Stochastic Host-Pathogen Tuberculosis Model with Adaptive Immune Response", Mathematical Problems in Engineering, vol. 2021, Article ID 8879538, 23 pages, 2021.

Exploring the Stochastic Host-Pathogen Tuberculosis Model with Adaptive Immune Response

Academic Editor: Juan P. Amezquita-Sanchez
Received18 Sep 2020
Revised14 Dec 2020
Accepted09 May 2021
Published19 Jun 2021


In this literature, we probe a stochastic host-pathogen tuberculosis model with the adaptive immune response of four states of epidemiological classification: Mycobacterium tuberculosis, uninfected macrophages, infected macrophages, and immune response CD4+ T cells. This model is pertinent to the latent stage of tuberculosis infection and active tuberculosis-infected individuals. The stochastic host-pathogen tuberculosis model in pathology is constituted based on the environmental influence on the Mycobacterium tuberculosis and macrophage population, elucidated by stochastic perturbations, and it is proportional to each state. We evince the existence and a unique global positive solution of a stochastic tuberculosis model. We attain sufficient conditions for the extinction of the tubercle bacillus. Moreover, we acquire the existence of the stationary distribution of the positive solutions by the Lyapunov function method. Eventually, numerical simulations validate analytical findings and the dynamics of the stochastic TB model.

1. Introduction

In the annals of history, there have been many threats such as natural calamity, diseases, and wild animals for the existence of humans; among these, diseases seem to be the main cause of death. In the previous centuries, tuberculosis posed a great threat to the survival of human beings. It is believed that it was the cause of death of more than a third population [1]. And block death in Europe is the standing testimony for these facts. Fortunately, due to the development of medical science, tuberculosis is completely curable but still persists.

Tuberculosis is traced back to 3400-2400 BC. It is as ancient as that of ancient countries such as Egypt, Greece, Rome, and India. The German Nobel laureate Robert Koch (1843–1910) discovered the tubercle bacillus (March 24, 1882) at the backdrop of one in seven who died in Europe due to mysterious disease.

Infection of the lungs bacteria (Mycobacterium tuberculosis (MTB)) leads to tuberculosis (TB). The bacterial infection may also spread into the brain, kidneys, spine, etc., but it is fortunate that tuberculosis is curable and preventable [1]. Tuberculosis is contagious and spreads through the air. Even the inhalation of a few of these germs is potential enough to infect a person. The physical contact, the nearness, and the air around the infected person can also infect. Sharing the same space with the infected person, weak immunity, malnutrition, unemployment, poor lifestyle, poor food habits, lack of shelter, unhygienic environment, drug abuse, imperfect sexual attitude, ill-literacy, and smoking are vulnerable factors for the spread of tuberculosis [2].

Infection is mainly occurred by the aerosol route like inhalation, wherein bacilli contained droplet nuclei sets in the alveoli. Here, alveolar macrophages [3] engulf the bacteria and ultimately bring out the infection to dendritic cells and all other cells as epithelial cells. These alveolar macrophages possess multiple microbicidal mechanisms which include phagolysosome fusion and respiratory burst to prevent postinfective mechanisms. For successful sustainability of infection, the tuberculosis bacilli must understand its encounter with the collection of activated macrophages (granuloma) [4, 5] and eventually gain access to the lymphocytes, neutrophils, fibroblasts, eosinophils, or the bloodstream [6, 7]. Macrophages with the potential to sterile and kill the bacteria are segmented apart in the tissue. In the case of adaptive immunity with the accumulation of effector CD4+ and CD8+ T cells setting in lungs, the multiplication of the bacterial population is contained and enumerable patients become asymptomatic and unable to shed bacteria, and they are then considered as vulnerable to latent TB infection (LTBI). Varied mechanisms cause the limited ability with adaptive immune responses to encounter and eradicate MTB, some of which are then categorized and characterized such as weakened histocompatibility complex (MHC) class II-mediated antigen presentation; adaptation of the anti-inflammatory mediator lipoxin A4; containing by regulatory T cells; monitoring bacterial antigen gene expression and hence incapable of reducing antigen-specific CD4+ T cells; and immune to the macrophages activating effector cytokines such as interferon- (INF-) and tumour necrosis factor- (TNF-) [4, 8].

The latent stage of the tuberculosis infection is nonchallenged; though the germs are present in the body, they are inactive and harmless. Antibiotics such as isoniazid (INH), rifampin (Rifadin, Rimactane), and rifapentine can also be used to contain the aggravation of the germs at this stage. It is very easy to wipe out the germs from the body at this stage. Indications of active tuberculosis infection are coughing, sudden weight loss, loss of appetite, sweating during nights, fever, and chest pain.

The potential roles for adjunctive immunotherapy in multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) [911] consist in enhancing cure rates and reducing time spent to cultural shifts, reducing the tissue damage concerned with nonproductive postimmune reactions, and elevating overall health status by subdoing systematic impacts of prolonged chronic inflammation. In addition, enumerable powerfully useful cytokines and other immunomodulatory agents already exist in medical use for other conditions.

A significant role in the immunity against pathogen agent is played by T-cell differentiation and memory and effector T cells [1214]. Hence, an effective T-cell response decides if the infection decreases or develops into a medically evident disease. Studies prove that CD4+ T cells [1315] do their part in the protection against MTB as strengthened by the evidence that CD4+ T cells such as T helper 1 (Th1), Th2, Th17, and regulatory T cells (Tregs) and all these subsets support one another to restrict infection. MTB-specific CD4+ Th1 cell response is recognized as possessing a protective role for the power to generate cytokines such as INF- and TNF- that involve the processes of recruitment and activation of innate immune cells as monocytes and granulocytes. In this way, when other antigen-specific T cells such as CD8+ cells [14], natural killer (NK) cells, T cells, nonclassical (MHC) class I molecule CD1, controlled T cells are able to raise INF- during MTB infection and they are unable to equalize the lack of CD4+ T cells.

Of late, studies have revealed that multifunctional/polyfunctional T cells (i.e., T cells possessed with multiple effector functions) [13, 14] can produce IFN- coupled with IL-2, and subsequently, a subset of cells is able to concurrently produce IFN-, TNF-, IL-2, and IL-17 and was diagnosed in patients with active TB disease compared to LTBI, which rapidly decreased on anti-TB treatment. And also, the polyfunctional T cells were recognized for their potentiality to proliferate and to secrete very many cytokines, and these cells were discovered to act a protective role in antiviral immunity in chronic infections (when the antigen load is low).

Memory T cells are a subset of infection-fighting T cells (T lymphocytes) that are highly proliferative and possess a strong immune response. Based on the role of L-selectin and CC-chemokine receptor 7, memory T cells can be segmented into and [1214]. In the case of in vitro stimulation, human memory CD4+T cells caused the production of IL-2 but hardly produce interferon-, IL-4, or IL-5. But cells rapidly produced these effector cytokines but produced little IL-2. cells named as central memory () cells [13, 14] are potential enough to produce numerous IL-2 but low lying of effector cytokines and home to secondary lymphoid tissues. But cells termed as effector memory () cells [14] are capable of producing high order of cytokines and home to peripheral tissues. Subsequently, there are various other subpopulations of memory T cells such as memory T stem cells (, multiple stem-like properties), T naive phenotype (), and transitional memory T cells () [13, 14], very many of which were secreted in the peripheral blood of healthy individuals.

Regulatory T cells () [16] are inevitable for monitoring peripheral tolerance, preventing self-generating immunity, and reducing chronic inflammatory disease. In fact, have varied mechanisms within their powers, and one such mechanism is the suppression by inhibitory cytokines which include IL-10, transforming (TGF-), and latest identified IL-35 which are prime mediators of cell function. CD4+CD25+FOXP3+ circulating play a primary role in restricting immune responses by downregulating CD4+ or CD8+ cell functions. Hectic suppression by is important in regulating immune responses against MTB.

In spite of the fact that the role of CD8 T cells [13] in TB is less clear than that of CD4 T cells, they are considered in general to impart optimal immunity and protection. CD8 T cells contain enumerable antimicrobial effector mechanisms that are less vital or cease to exist in CD4 Th1 and Th17 T cells. CD8 T cells emit cytokines or cytotoxic molecules, which cause apoptosis of target cells. Th1 CD4 T cells propel effector functions in macrophages that contain intracellular MTB, and their role has been monitored with protection. Besides, many studies have depicted that Th17 cells, which can produce IL-17, are implicated in immune protection against MTB, mainly due to the effect of this cytokine in incurring and vibrating neutrophils. Th 17 cells have been implicated in the protection against TB at initial levels, for their power to employ monocytes and Th1 lymphocytes to the space of granuloma formation [5]. Contrarily, very many studies have manifested that unrestricted Th17 stimulation confirms an exaggerated inflammation catalyzed by neutrophils and inflammatory monocytes that rush to the place of disease during the damage of tissue.

MTB-specific CD4+ T-cell protective response is simply due to Th1 cells and is negotiated by IFN- and TNF- that employ monocytes and granulocytes and enhance their antimicrobial attitudes. Subsequently, higher part of antigen-specific effector memory cells and diminished frequency of central memory CD4+ T cells have been discovered in patients with active TB in comparison with distribution witness in LTBI individuals. All the information converges on the increase of this complicated disease with the aim of improving diagnosis, prognosis, drug therapy, and vaccination.

Zhang [17] acclaimed the following host tuberculosis model:

The biological meaning of all positive parameters and symbols in the deterministic TB model (1) are listed in Table 1. According to the theory in [17], the deterministic TB model (1) has the following properties:


Mycobacterium tuberculosis (MTB) population at time
Population of uninfected macrophages at time
Population of infected macrophages at time
Population of immune response CD4+ T cells at time
Bacterium growth rate
Carrying capacity
Death rate of infected macrophages
Extracellular bacteria rate by burst
Engulfment rate of uninfected macrophages
Half saturation rate in uninfected macrophages
Killing rate of extracellular bacteria
Influx rate of uninfected macrophages
Death rates of uninfected macrophages
Infection rates of uninfected macrophages
Killing rate of infected macrophages
Cell-mediated adaptive immune response rate
Natural recruitment rate of activated CD4+ T cells
Maximum killing rates of extracellular bacteria macrophages
Maximum killing rates of infected macrophages
Saturating factor of extracellular bacteria macrophages
Saturating factor of infected macrophages
Death rate of activated CD4+ T cells

The positive invariant set Γ is given byThe disease-free equilibrium is given by .If , then the disease-free equilibrium is globally asymptotically stable, where .The tuberculosis model (1) has a unique positive infected equilibrium if and only if and it is globally asymptotically stable when it exists. The positive infected equilibrium , where , andand is determined by

In reality, the environmental noise perverts through and medal with the population dynamics, ecology, environmental sciences, and mathematical biology. Stochasticity has its impact upon various biological [1825] and other models [2630]. Many researchers probed stochastic tuberculosis models in which the total host population can be divided into three, four, and five epidemiological classes, respectively, such as susceptible , exposed , and infected [31]; susceptible , latent , infectious , and treated [32]; susceptible , exposed , infected , and recovered [33]; and susceptible , vaccinated , infected with TB in latent stage , infected with TB in active stage , and treated individuals infected with TB [34, 35]. On the other hand, Khalid Hattaf et al. [36, 37] investigated specific functional response and temporary immunity and delayed viral infection models with adaptive immune response like cytotoxic T lymphocyte (CTL) cells which is in MHC class I molecules. In all the above models such as , the researchers probed on host population, temporary immunity, and CTL cells. However, the authors have not examined the functions of macrophages and immune response CD4+ T cells which are in MHC class II molecules so far.

The macrophages inundate the MTB and quarantine them in a cellular compartment where the bacteria are killed or cannot thrive. If the number of MTB is higher than that of macrophages, it will result in the death of the macrophages in the granuloma. Then the granuloma’s core liquidizes and is transmitted through airways to other people. During infection, the MTB cells set sporadically in the alveoli of an individual. The immunologic effects of both infected and uninfected macrophages vary randomly due to environmental sources of MTB. The adaptive immune responses in an individual start with very few number of cells and later vary greatly among individual immune systems. This variation is random, and on the other hand, individuals with smoking habit, weak immunity, malnutrition, etc., possess low immune response and have to be treated with more dosages of antigens to increase the immunity contingently.

This study is challenging and useful in the sense that TB in its various dimensions and nature can be disclosed. Based on the above factors, we put forth the stochastic host-pathogen TB model with adaptive immune response. The stochastic host-pathogen TB model on the basis of the influence of the environment on the Mycobacterium tuberculosis and macrophage population was manifested by stochastic perturbations and it is proportional to each state [38, 39].

We establish the following stochastic host-pathogen TB model:

Let be a 4-dimensional Wiener process defined on the given probability space. The components of are supposed to be mutually independent. In the stochastic model (5), the nonnegative constants , and denote the intensities of the environmental white noise.

The intention of this literature is structured as follows. In Section 2, the existence of the global and positive solutions to the stochastic host-pathogen TB model (5) is examined. In Section 3, sufficient conditions for the extinction of the tubercle bacillus are probed. In Section 4, we probe that there is a unique ergodic stationary distribution of the positive solutions of the stochastic TB model (5) under some conditions. In Section 5, we demonstrate some numerical simulations that validate our analytical findings. Eventually, Section 6 provides conclusions and future directions.

2. Global Positive Solutions of the Stochastic TB Model

Since , and in the stochastic TB system (5) denotes the population of MTB, uninfected macrophages, infected macrophages, and immune response CD4+ T cells, respectively, they should be nonnegative. For a stochastic differential equation to have a unique global (i.e., no explosion in a finite time) solution for any given initial value, the coefficients of the equation are eventually required to satisfy the linear growth condition and local Lipschitz condition. Yet, the coefficients of equation (5) do not satisfy the linear growth condition; nevertheless, they are locally Lipschitz continuous, and thus, the solution of equation (5) may explode at a finite time. Hence, for further studies, we should set some preconditions under which stochastic system (5) has unique global positive solutions.

Theorem 1. For any given initial value , there exists unique positive solutions of the stochastic TB model (5) on and the solution will remain in with probability one.

Proof. It is clear that the stochastic TB system (5) satisfies the local Lipschitz condition for any given initial value . Then, there exist unique maximum local solutions on , where is the explosion time [43]. To exhibit that the solution is universal, i.e., inevitable to affirm that a.s. Basically, we exhibit that , and do not explode to infinity in a finite time. Let be adequately large . For each integer , define the stopping time [40]:with the typical format , where reflects the empty set. Evidently, is increasing as . We have ; therefore, a.s. If we evince that a.s., then and a.s. for all . Presume that , then there is a pair of constants and such thatThus, there exists an integer such thatDefine a -function bywhere and will be determined later. The nonnegativity of function occurs from .
By Itô’s formula to , we obtainwhere is defined asChoose such that and let such that , and then we havewhere is a positive constant. Thus,Integrate both sides of equation (13) from 0 to ,Taking expectations on both sides of (14) yieldsLet for all , and by (8), then . Notice that for every , there exists at least or or or which is equal to either or .
If or , thenSimilarly, if or , thenIf or , thenIf or , thenTherefore,Then, we attainwhere is the indicator function of . Letting , we get . It is a contradiction, and hence, we obtain a.s., which completes the proof of Theorem 1.

Remark 1. Considering the region is positively invariant, the unique solution of the stochastic TB model (5) exists for any given initial value in . Hence, it is sufficient to probe its dynamics of the host-pathogen stochastic TB model in the region .

Remark 2. As stated in the introduction, immunotherapy with LTBI and active TB individuals and adaptive immune responses are known to be quite effective against MTB. However, the prevailing opinion among public health and medical practitioners in the entire world, prior to 1944 [44], was a less effective treatment for TB patients. During the years between 2016 and 2035, the efforts at the global, regional, and national levels to ease and eradicate the burden of TB disease have the colossus objective “ceasing TB epidemic,” within the purview of the UN’s Agenda for Sustainable Development and based on the WHO’s End TB Strategy [1]. Hence, it is fruitful to study the eradication of the MTB among LTBI and active TB individuals. This is done as follows.

3. Extinction of the MTB

In this section, the extinction of the MTB is discussed. The death rate of uninfected macrophages and the intensities of the white noise in the stochastic system (5) are the consequences of the random fluctuations. The population dynamics show direct results on the qualitative outcome of the MTB dynamics in the system with regard to the factors that decide MTB eradication during the long course of time. Firstly, we shall present a lemma which will be used in our analysis.

Lemma 1. Let be the solution of the stochastic TB system (5) with any positive initial value . ThenMoreover, if , then

Define a parameter as follows:

Theorem 2. For any given initial value , then the MTB of the stochastic TB system (5) will cease out if and , i.e., a.s.

Proof. Consider the second and third equations of the stochastic TB system (5). Integrating these equations from 0 to and dividing both sides by , we getIt follows thatConsequently,By Lemma 1, we haveOn the other hand, let .
Applying Itô’s formula, we obtainwhere and .
Integrating both sides of (28) from 0 to , we attainDividing both sides of by and then taking the limit superior yieldThe conclusion is confirmed.

Remark 3. The immunomodulatory agents are compatible to immune responses such as IL-2 and IL-4 to effectively active T helper cells. Immunosuppressive agents such as TNF- moderate dangerous inflammation and cytokine therapy INF- tends to accelerate the mycobacterial activity of effector immune cells [42]. All these facts exist in reality, which wipe out the MTB.

Remark 4. Patients have lack of information, lack of money for treatment, side effects, lack of commitment to a long course, social barriers, irregular treatment and do not take proper drugs and so they have a low level of immunity. These are the factors for the TB persistent and prevalence among population.

4. Ergodic Stationary Distribution

When considering epidemic dynamical systems, we are interested in when the disease will persist and prevail in a population. In this section, we present some theories about the stationary distribution (see Has’minskii [43]), and we show that there exists an ergodic stationary distribution, which reveals that the disease will persist. Let be a homogeneous Markov process in , which is described by the following stochastic differential equation:

The diffusion matrix is defined as follows:

Lemma 2 (see [39]). The Markov process has a unique ergodic stationary distribution if there exists a bounded domain with regular boundary , having the following properties:: there is a positive number such that .: there exist a nonnegative -function and a positive constant such that for any . Thenfor all , where is a function integrable with respect to the measure .

Define a parameter

Theorem 3. Assume that , then for any initial value , the stochastic TB system (5) admits a unique stationary distribution and it has the ergodic property.

Proof. The diffusion matrix of the stochastic TB system (5) is given bySelect , and we havewhere and is an adequately larger integer, and then condition in Lemma 2 holds.
Next, we tend to prove the condition . Definewhere and are positive constants to be resolved later. By applying Itô’s formula to , we getChooseThenDefinewhere , and are positive constants to be determined later. By calculating,