Nepal Journal of Biotechnology. D e c . 2 0 1 7 Vol. 5, No. 1: 46- 57 ISSN 2091-1130(Print)/ISSN 2467-9319 (online)

REVIE W ARTICLE

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Apoptosis: Implications in Viral and Mycobacterium
tuberculosis infections

Gorakh Raj Giriǂ, Uddhav Timilsinaǂ*

Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India

Abstract
Apoptosis is a form of programmed cell death leading to genetically controlled self-destruction of cells. It is

essential in the development, maintenance, and regulation of cells during physiological as well as pathological

conditions. Deregulation of apoptotic mechanisms is associated with various pathological diseases including

cancer, autoimmune disorders, viral and bacterial infections. Virus and Mycobacterium tuberculosis elicit host cell

apoptosis as a part of host immune defense or pathogen dissemination. They inhibit both extrinsic and intrinsic

pathways of apoptotic mechanisms facilitating pathogen survival and escape from host immune defense.

Keywords: apoptosis, virus, Mycobacterium tuberculosis, immune response

*Corresponding Author

Email: timilsinau@gmail.com

Introduction
Apoptosis is a form of programmed cell death

which is the most common form of physiological

cell death in eukaryotes, evolutionarily conserved

from yeast to humans. It leads to the genetically

controlled sequence of events that eventually give

rise to spatially and temporally regulated self-

destruction of cells [1,2]. Apoptotic mode of cell

death is an active process, critical in the

development of multicellular organisms and the

maintenance and regulation of cell populations

during physiological and pathological conditions

[3,4]. Deregulation of apoptosis leads to various

pathological conditions including cancer,

autoimmune disorders, and spreading of viral

infections while AIDS, Neurodegenerative

disorders, and ischemic diseases are caused or

enhanced by accelerated apoptosis [3,5–8]. Both

viral and Mycobacterium tuberculosis (Mtb)

infections modulate host cell apoptosis for their

benefits [6,9–11]. This review briefly summarizes

the mechanisms of apoptotic deaths and their

regulation and significances in viral and

mycobacterial infections.

Apoptosis
Various extracellular and intracellular stimuli

trigger apoptosis. Ligation of cell surface

receptors, DNA damage (because of defects in

DNA repair mechanism, cytotoxic drugs, or

irradiation), lack of survival signals, contradictory

cell cycle signaling or developmental death signals

are some of the signals evoking apoptosis [1].

Apoptosis depends on the activation of a

proteolytic cascade of pro-caspases into active

caspases. These caspases are synthesized in cells

as inactive zymogens called as pro-caspases. Pro-

caspases are cleaved by pre active caspases at one

or two specific aspartic acids splitting them into

two subunits, one small and another large. The

assembly of two heterodimers of small and large

subunits results in the formation of active

caspases. The pro-caspases fall into two classes-

initiator and executioner [12,13]. Apoptotic stimuli

trigger activation of initiator caspases (caspases 2,

8, 9, 10) which in turn cleave and activate the

executioner caspases (caspases 3, 6, 7) [14]. The

executioner caspases cleave thousands of

substrates responsible for the characteristic

morphological and biochemical features of

apoptotic cells [14]. The three main established

routes of apoptosis in mammals are extrinsic,

intrinsic and perforin/granzyme pathways [2,15].

Irrespective of the death stimuli or apoptotic

paths, all the three routes lead to the activation of

executioner caspases 3, 6 and 7 (Figure 1).

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Figure 1. Diagram showing general apoptosis process through three main pathways: Extrinsic (death receptor-
mediated viz. FasL, Fas, Trail-R1, and R2) pathway, intrinsic (mitochondria-dependent) pathway and perforin
(granzyme)-mediated pathway. The extrinsic pathway starts with the binding of death receptor ligand (DR ligand) to
the cell surface death receptors including tissue necrosis factor (TNF) receptor superfamily include CD95 and TNF-
related apoptosis-inducing ligand (TRAIL)-R1/-R2, with the rapid activation of the initiator caspase 8. In the intrinsic
pathway, stress (reactive oxygen species, ROS, UV, genotoxic stress, etc.) results in the perturbation of mitochondria
membrane permeability, release of the proteins such as cytochrome c from the inner mitochondrial membrane space.
The release is regulated in part by Bcl2 family members, with anti-apoptotic (Bcl2/Bcl—XL/Mcl1) and pro-apoptotic
(Bax, Bak, and tBid). Once released, cytochrome c binds to apoptotic protease-activating factor 1 (Apaf1), which results
in the formation of the Apaf1-caspase 9 apoptosome complex and activation of the initiator caspase 9. The activated
initiator Caspases 8 and 9 then activate the effector caspase 3, 6 and7 with normal cell apoptosis or another T-cell
effector mechanism. Cytotoxic T lymphocytes (CTL) or natural killer (NK) cells secrete the transmembrane pore-
forming molecule perforin and release cytoplasmic granules (Granzyme A/B) into tumor cells or virus-infected cells.
Granzyme A activates DNA degradation by DNase NM23-H1while granzyme B cleaves pro-caspase 8, pro-caspase 3 or
Bid.

Extrinsic pathway of apoptosis
External apoptotic signaling mediates the

activation of transmembrane death receptors that

transmit apoptotic signals after binding to

extracellular death ligands such as FasL or tumor

necrosis factor-α (TNFα) [16]. Death receptors

belong to tumor necrosis factor receptor (TNFR)

superfamily including TNFR-1, Fas/CD95 and

TNF receptor-related apoptosis-inducing ligand

(TRAIL) receptors DR-4 and DR-5 [17]. Proteins of

TNFR family result in trimerization and activation

of intracellular death domain after ligand binding.

Adaptor proteins like FADD or TRADD get

recruited through their death domains to the

death domains of activated death receptors

forming death inducing silencing complex (DISC).

Death effector domains of FADD or TRADD

recruit pro-caspase 8 leading to their autocatalytic

activation and release of active caspase 8.

Activated caspase 8 then cleaves and activates

downstream executioner caspases 3 and 7. In some

cases, the extrinsic death signals can crosstalk with

an intrinsic pathway through caspase 8-mediated

proteolysis of the BH3-only protein Bid. Truncated

Bid can translocate to mitochondria and induce

the release of cytochrome c and assembly of

apoptosome triggering activation of pro-caspase 9

[18–20] (Figure 1).

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Intrinsic pathway of apoptosis
Intracellular death signals such as DNA damage,

oxidative stress, starvation and others trigger

intracellular apoptotic pathway. All of these

stimuli cause changes in inner mitochondrial

membrane resulting in the opening of the

mitochondrial permeability transition (MPT) pore,

loss of the mitochondrial transmembrane potential

(ΔΨm) and release of two groups of pro-apoptotic

proteins from the intermembrane space into the

cytosol [21]. The first group of released proteins

constitutes cytochrome c, Smac/DIABLO, and the

serine protease HtrA2/Omi that promotes

caspase-dependent mitochondrial pathway [22–

24]. Cytochrome c binds and activates Apaf-1

(apoptosis protease activating factor 1) which

hydrolyzes bound dATP to dADP. Replacement of

dADP with dATP/ATP leads to Apaf-1-

cytochrome c complex to oligomerize into a wheel

like a heptamer called apoptosome. Pro-caspase 9

gets recruited in the apoptosome through its

caspase recruitment domain (CARD) [25] and gets

activated and cleaved which then triggers

activation of downstream executioner caspases

(Figure 1) [25]. Smac/DIABLO and the serine

protease HtrA2/Omi, on the other hand promote

apoptosis by inhibiting IAP (inhibitors of

apoptosis) proteins [23,24]. The second group of

released proteins includes AIF, endonuclease G,

and CAD which translocate to the nucleus and

cause DNA fragmentation and condensation of

peripheral nuclear chromatin [26–28]. In addition

to the release of mitochondrial factors, the loss of

the ΔΨm leads to regulation of biochemical

homeostasis of the cell viz. ATP synthesis gets

stopped, redox molecules like NADH, NADPH

and glutathione are oxidized, and reactive oxygen

species are enhanced [29–32].

Perforin/ Granzyme pathway of
apoptosis
Cytotoxic T lymphocytes (CTL) or natural killer
(NK) cells can exert their cytotoxic effects on
tumor cells and virus-infected cells by secretion of
the transmembrane pore-forming molecule
perforin with the subsequent release of
cytoplasmic granules through the pore into the
target cell [33]. These granules constitute the

serine proteases granzyme A and B. Granzyme B
can cleave proteins at aspartate residues and thus
activate pro-caspase 8 and Bid. Direct activation
of pro-caspase 3 and cleavage of ICAD could also
be the results of granzyme B. Thus granzyme B
dependent routes of apoptosis may be
mitochondrial or direct [26]. Granzyme A activates
caspase-independent apoptosis [34] (Figure 1).
Inside the cell, it enables DNA degradation by
DNase NM23-H1. Granzyme A cleaves SET
complex (nucleosome assembly protein that
usually inhibits DNase NM23-H1 gene) thereby
releasing the inhibition of DNase NM23-H1
leading to DNA degradation [34].

Regulation of apoptosis
The components of apoptotic pathways are

genetically encoded and ready for action. Most

cells are just waiting for the death stimuli to

trigger these pathways. Thus a tight regulation of

apoptosis is mandatory. B-cell lymphoma-2 (Bcl-2)

family proteins play a crucial role in the regulation

of apoptosis through their ability to control

mitochondrial permeability [35]. Bcl-2 family

comprises three subfamilies that contain between

one and four Bcl-2 homology (BH) domains. Anti-

apoptotic Bcl-2 subfamily includes four BH

domains, and most of them are membrane-

associated proteins. The pro-apoptotic Bax-like

subfamily comprises membrane-associated

proteins that lack BH4 domains, while the BH3-

only subfamily includes a diverse group of

proteins containing only BH3 domains [36]. The

mammalian BH3-only protein family currently

consists of eight members (Bid, Bad, Bim, Bak, Bik,

NOXA, PUMA, and HRK). Among eight

members, NOXA, PUMA, and Bid are

transcriptionally upregulated by p53. Bid is

activated by caspase 8-dependent proteolysis.

Phosphorylated Bad is trapped by 14-3-3 protein

and sequestered in the cytoplasm. Once Bad is

unphosphorylated, it gets freed and is

translocated to mitochondria. Bim and BMF are

microtubules, and actin microfilaments tethered

proteins and disruption of cytoskeleton liberates

them [37,38]. The anti-apoptotic Bcl-2 family of

proteins (Bcl-2, Bcl-XL, Bcl-W, Mcl1, Bcl2A1 and

Bcl-B) blocks apoptosis by preventing BH3-only

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Table 1: List of viral and Mtb proteins involved in apoptosis deregulation

Viruses/Mtb (proteins) Modulation in apoptotic process References

Adenovirus proteins (E3-10.4K
and E3-14.5K)

Reduce Fas presentation, inhibit TNF-mediated apoptosis

[42, 43]

Epstein-Barr virus LMP-1 protein Acts like constitutively activated TNF receptor [44]

Myxoma virus protein M-T2 Viral mimic protein of TNF receptor [45]

Cowpox virus CRM protein Prevents TNF-mediated apoptosis [46]

Vaccinia virus protein A53R Prevents TNF-mediated apoptosis [47]

HIV-1 Tat Decreases susceptibility to TRAIL, TNFα, and Fas.
Upregulates FasL, Bax, caspase 8 and RCAS-1 expression,
upregulates Bcl2 and c-FLIP expression, downregulates
caspase 10 expression

[50,68-72]

Herpesviruses: FLICE Inhibits DISC formation [51]

Human Cytomegalovirus: vICA Inhibits caspase 8 [52]

SV40 virus large T antigen Binds to and sequesters p53 [53]

Human papillomavirus E6 protein p53 ubiquitination and degradation [55]

Adenovirus E1B-55K protein p53 ubiquitination and degradation [56]

Adenovirus E1B-19K Binds to Bak preventing Bax-Bak oligomerization [56]

Human herpesviruses: Bcl-2 ortholog Blocks the mitochondrial release of cytochrome c [59]

Epstein-Barr virus: Bcl-2 ortholog Blocks the mitochondrial release of cytochrome c [60]

Kaposi’s sarcoma-associated γ-herpes
virus: Bcl-2 ortholog

Blocks the mitochondrial release of cytochrome c [59]

Human CMV protein: vMIA Inhibits Fas-mediated apoptosis [61,62]

Poxviruses serpin CrmA Suppresses caspase 1 and 8, inhibits TNF and Fas-mediated
apoptosis

[63]

Baculovirus protein p35 Inhibits caspases 1, 3, 6, 7, 8 and 10 [64,65]

African swine flu virus: vIAP Inhibits caspase 3 [66]

HIV-1 gp120 Syncytia formation, upregulates Fas, FasL, and TNFα
expression, upregulates TRAIL receptors: DR4 and DR5, acts
as a molecular mimic of Fas, reduces expression of Bcl2,
phosphorylates mTOR and p53, increases expression of
PUMA and activates p38

[48,67]

HIV-1 Nef Increases the membrane expression of TNF [49]

Hepatitis B virus pX protein Inactivates p53 [57]

West Nile capsid protein Binds to and sequesters p53 [54]

Arenaviruses matrix protein Z Activation of BH3-only proteins?, an indirect interaction
with p53 and PI3K/Akt with the help of PML?

[74-78]

Enterovirus 71 2B protein Direct interaction with and activation of Bax [80,81]

Mtb proteins
(Mcl-1, A1?)

Upregulates TNF, Fas, and caspase 8 expression, stimulates
ROS-dependent activation of apoptosis signal-regulating
kinase, phosphorylates and degrades FLIP, MOMP-
mediated apoptosis, upregulates FLIP expression, secretes
more sTNFR2, increases expression of anti-apoptotic protein
Bcl-w, inhibition of the pro-apoptotic protein Bad

[101,104-
106, 113-
115]

? Refers to mechanism not yet verified.

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protein induced oligomerization of the pro-

apoptotic Bcl-2 proteins Bax and Bak in the

mitochondrial outer membrane. Some BH3-only

proteins (Bid and Bim) interact with almost all

anti-apoptotic Bcl-2 proteins whereas others

(NOXA) interact only with specific Bcl-2 members

[35,37,38].

In conclusion, under distinct apoptotic stress

signals, BH3-only proteins interfere the fine-tuned

balance of homo or hetero-oligomerization

between pro-apoptotic members Bax/Bak and

anti-apoptotic members Bcl-2/Bcl-XL and release

the intermembrane space proteins like cytochrome

c to trigger apoptosis.IAPs (inhibitors of apoptosis

proteins) are a family of proteins having anti-

apoptotic activity [32]. Including NAIP, c-IAP1, c-

IAP2, XIAP, and survivin, there are eight human

IAP homologs. XIAP, c-IAP1, and c-IAP2 directly

inhibit caspases 3, 7, and 9. Smac/Diablo, when

released from mitochondria, binds to XIAP and

releases caspases from XIAP-caspase complex

thereby enabling their activation [39,40]. The

cellular FLICE-like inhibitory proteins (c-FLIPs)

inhibit activation of caspase 8 and thus prevent

apoptosis [34].

Virus-mediated modulation of apoptosis
In most cases of viral infections, immune and

inflammatory responses, as well as apoptosis of

the infected host cell, are triggered. Meanwhile,

some viruses utilize apoptosis as a mechanism of

killing cells and spreading virus by targeting a

variety of crucial steps in the pathways that block

or delay apoptosis. Thus viral infection elicits host

cell apoptosis as a part of host immune defense or

viral survival component [41].

Virus modulates the extrinsic pathway
of apoptosis
Many viruses can efficiently modulate the

extrinsic pathway of apoptosis. Adenovirus

proteins E3-10.4K and E3-14.5K reduce the

presentation of Fas molecules on the surface of the

cells that results in resistance to Fas-mediated cell

death [42]. These proteins also resist TNF-

mediated apoptosis [43]. Epstein-Barr virus LMP-1

(latent membrane-1) protein acts like

constitutively activated TNF receptor which

interacts with TNF receptor-associated death

domain (TRADD) protein [44]. The myxoma virus

protein M-T2, a viral mimic protein of TNF

receptor, Cowpox virus cytokine response

modifying (CRM) proteins and vaccinia virus

protein A53R inhibits TNF-mediated apoptosis

[45, 46, 47]. Membrane-bound HIV-1 gp120

induces apoptosis through syncytia formation

while it triggers apoptosis by various mechanisms

like upregulation of Fas, FasL, and TNFα

expression, upregulation of TRAIL receptors DR4

and DR5, and acting as a molecular mimic of Fas

[48]. HIV-1 Nef protein downregulates the

expression of CD4 and MHC I molecules but

heightens the membrane expression of TNF and

related cytokines [49]. HIV-1 Tat mediates

apoptotic resistance in the infected cells by

decreasing susceptibility to TRAIL, TNFα, and

Fas, but it reconciles apoptosis in uninfected

bystander cells by upregulation of FasL [50].

Various herpes viruses encode viral FLICE-like

inhibitory proteins (FLIPs), which contain death

effector domain but lack caspase activity, inhibit

extrinsic apoptotic pathway at the point of DISC

formation [51]. The human cytomegalovirus

encodes vICA, which associates with caspase 8

and blocks its activation [52] (Table 1).

Virus modulates the intrinsic pathway of
apoptosis
Many viruses alter apoptosis utilizing the tumor

suppressor p53. SV40 virus large T antigen and

West Nile capsid protein binds to p53 and

sequesters it in an inactive complex [53,54].

Moreover, Human papillomavirus E6 protein and

adenovirus E1B-55K protein promote ubiquitin

mediated degradation of p53 [55,56] and Hepatitis

B virus pX protein binds and inactivates p53 [57].

Virus-encoded orthologs of anti-apoptotic Bcl2

proteins are also crucial players in the modulation

of apoptosis. Adenovirus E1B-19K is similar to

Bcl2 which binds to Bak preventing Bax-Bak

oligomerization [58]. Human herpes viruses,

Epstein-Barr virus and Kaposi’s sarcoma-

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associated γ-herpes virus use Bcl-2 orthologs to

block the mitochondrial release of cytochrome c

[59,60]. Although human cytomegalovirus (CMV)

protein vMIA shares no sequence homology to

Bcl2, it is functionally similar to Bcl-2 and inhibits

Fas-mediated apoptosis [61,62]. Some viruses use

IAP orthologs that can inhibit caspases. For

example, Poxviruses serpin CrmA suppresses

caspase 1 and 8 and inhibits TNF and Fas-

mediated apoptosis [63]. Likewise, African swine

flu virus produces vIAP that inhibits caspase 3

and Baculovirus protein p35 is another vIAP with

a potential to inhibit caspases 1, 3, 6, 7, 8 and 10

[64,65,66]. HIV-1 gp120 triggers apoptosis by

reduced expression of Bcl2, phosphorylation of

mTOR and p53, increased expression of pro-

apoptotic protein PUMA and activation of p38

[67]. HIV-1 Tat inhibits apoptosis in infected cells

by upregulation of Bcl2 and c-FLIP expression

[68,69] and downregulation of caspase 10

expression [70]. The same protein triggers

apoptosis in bystander cells by upregulation of

Bax, caspase 8 and RCAS-1 expression [71,72], and

Bim-mediated intrinsic apoptosis [73]. Matrix

protein Z of some arenaviruses (New World

arenavirus, Tacarible virus (TCRV), and the

attenuated vaccine strain of Junín virus (JUNV)

Candid #1) activates caspase 9 thereby triggering

the intrinsic apoptotic pathway [74,75]. Though

the exact molecular mechanism of viral protein Z-

mediated apoptosis is still not clear, in vitro

experiments suggest a direct activation of BH3-

only proteins and an indirect interaction with

proteins like p53 and PI3K/Akt through cellular

oncoprotein promyelocyte leukemia protein

(PML) [74–76]. The Old World arenaviruses, the

lymphocytic choriomeningitis virus (LCMB) and

Lassa virus (LASV) do not cause apoptosis of

infected cells [77,78]. Caspase-mediated cleavage

of nucleoproteins (NPs) of Old World

areanviruses generates multiple truncated

isoforms of NPs [74,79]. A decoy function of NPs

has been proposed in which the cleavage of highly

expressed NPs within the cell suppresses the

cellular targets of caspases thereby inhibiting the

apoptosis of the infected cell [74]. Enterovirus 71

2B protein directly interacts with and activates the

proapoptotic protein Bax leading to the activation

of mitochondrial pathway of apoptosis [80,81]

(Table 1).

Mycobacterium-mediated modulation of
apoptosis
Bacterial pathogens are known to have anti-

apoptotic mechanisms. Mycobacterium tuberculosis

(Mtb) causes persistent infection indicating that it

employs effective mechanisms to inhibit host cell

death [82]. Published studies highlight both pro-

apoptotic as well as anti-apoptotic capabilities of

virulent Mtb [83,84], however the underlining

molecular mechanisms are still not well

understood. Though there is a lack of published

data favoring Mtb-mediated apoptosis of host

cells, increased apoptosis of primary human

macrophages or human macrophage-like cell lines

(U937 and THP1) were reported upon infection

with virulent Mtb in vitro [85–87]. Human alveolar

macrophage-derived from bronchoalveolar lavage

of tuberculosis patients also showed increased

apoptotic death compared to healthy subjects

[88,89]. Apoptosis of Mtb infected cells

accompanied by the recruitment of uninfected

macrophages through upregulation of MMP9 on

epithelial cells surrounding the granuloma helps

in the dissemination of the bacteria [90]. In the

studies involving the zebrafish and mouse lung

models, the pro-apoptotic nuoG Mtb mutant

induced enhance innate response, longer survival

and rapid dissemination of the bacteria [91,92].

Thus, evidence suggests that host cell apoptosis is

crucial for host resistance to Mtb infection.

Considerable less apoptosis of human alveolar

macrophage or macrophage-like cell lines when

infected with virulent Mtb compared to infection

with less virulent strains was reported [93–96].

Furthermore, fact that inhibition of apoptosis of

human and murine macrophages by Apoptosis-

inducing species M. kansaii after over-expression

of Mtb-nuoG/SecA2/PknE [97–99] and resistance

to FasL and TNFα-mediated apoptosis of Mtb

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infected cells provide the evidence that Mtb

inhibits host cell apoptosis [100].

Mtb modulates the extrinsic pathway of
apoptosis
Gene expression profiling study suggests that

numerous apoptosis-related genes are down-

regulated in active tuberculosis patients compared

to latently infected subjects. Though expressions

of TNF, Fas, and caspase 8 upregulate in active

tuberculosis patients, simultaneous marked

expression of FLIP, inhibits host cell apoptosis

[101]. Mtb infected macrophages are known to

secrete more soluble TNF receptor 2 (sTNFR2)

which binds to TNFα thereby inhibiting its

binding with the TNFR1 [100,102–104]. Upon

infection with Mtb, TNF production in the mouse

cell line RAW264 stimulates ROS-dependent

activation of apoptosis signal-regulating kinase

thereby phosphorylating FLIP [105]. Ubiquitin-

proteasome-mediated degradation of

phosphorylated FLIP activates caspase 8 leading

to apoptosis [105] (Table 1).

Mtb modulates the intrinsic pathway of
apoptosis
Mtb infection upregulates the expression of anti-

apoptotic genes like mcl-1 and A1, both of which

encodes for anti-apoptotic Bcl-2-like proteins [106–

110]. Alternative splicing gives rise to two

isoforms of Myloid cell leukemia-1 (Mcl-1)

protein. One is the anti-apoptotic full length Mcl-

1L that possesses BH domains 1, 2 and 3 and a

transmembrane domain. Another is the pro-

apoptotic short variant Mcl-1S that lacks BH1, BH2

and the transmembrane domain. Mcl-1S dimerizes

with and antagonizes the function of Mcl-1L

thereby regulates the mitochondrial permeability

[109,111]. Furthermore, chemical inhibition of Mcl-

1 in mouse peritoneal macrophages infected with

Mtb significantly triggered apoptosis [112]. It will

be interesting to dissect the role of both isoforms

of Mcl-1 in Mtb-mediated apoptosis evasion. Also,

the expression of anti-apoptotic protein Bcl-w gets

upregulated [113], while the inactivation of the

pro-apoptotic Bad protein occurs upon Mtb-

H37Rv infection [114]. Infection of macrophages

with attenuated Mtb leads to MOMP-mediated

apoptosis without MPT induction [10,115] (Table

1). In contrast, macrophages infected with virulent

Mtb induce both MOMP and MPT causing

irreversible mitochondrial swelling leading to

necrosis [115].

Conclusion
Programmed cell death via apoptosis is crucial in

maintaining cells in health and pathological

conditions. Both viral and Mtb infections

modulate the apoptotic pathways of infected as

well as neighboring bystander cells. Though the

majority of virally infected cells undergo

apoptosis favoring viral dissemination, viral

proteins help specific host cells to evade apoptosis

thereby preferring viral persistence. Mtb infection

prominently evades host cell apoptosis leading to

the persistent survival of the pathogen.

Understanding the molecular mechanisms of

deregulation of apoptosis in viral and Mtb

infection may provide insights into revealing new

targets for curing these pathological conditions.

Conflict of Interest
Both authors declare that there is no conflict of

interest.

Authors Contribution
Both authors contributed equally to this work

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