Inhibition Of Host Cell Apoptosis Research Articles

Microsporidian Nosema bombycis secretes serine protease inhibitor to suppress host cell apoptosis via Caspase BmICE.

Microsporidia are a group of intracellular pathogens that actively manipulate host cell biological processes to facilitate their intracellular niche. Apoptosis is an important defense mechanism by which host cell control intracellular pathogens. Microsporidia modulating host cell apoptosis has been reported previously, however the molecular mechanism is not yet clear. In this report, we describe that the microsporidia Nosema bombycis inhibits apoptosis of Bombyx mori cells through a secreted protein NbSPN14, which is a serine protease inhibitor (Serpin). An immunofluorescent assay demonstrated that upon infection with N. bombycis, NbSPN14 was initially found in the B. mori cell cytoplasm and then became enriched in the host cell nucleus. Overexpression and RNA-interference (RNAi) of NbSPN14 in B. mori' embryo cell confirmed that NbSPN14 inhibited host cells apoptosis. Immunofluorescent and Co-IP assays verified the co-localization and interaction of NbSPN14 with the BmICE, the Caspase 3 homolog in B. mori. Knocking out of BmICE or mutating the BmICE-interacting P1 site of NbSPN14, eliminated the localization of NbSPN14 into the host nucleus and prevented the apoptosis-inhibiting effect of NbSPN14, which also proved that the interaction between BmICE and NbSPN14 occurred in host cytoplasm and the NbSPN14 translocation into host cell nucleus is depends on BmICE. These data elucidate that N. bombycis secretory protein NbSPN14 inhibits host cell apoptosis by directly inhibiting the Caspase protease BmICE, which provides an important insight for understanding pathogen-host interactions and a potential therapeutic target for N. bombycis proliferation.

Immune System Responses against Mycobacterium tuberculosis and its Mechanisms to Escape from the Immune System

Background: Mycobacterium tuberculosis (MTB) employs a variety of strategies to evade the host immune response, enabling its persistence and the development of tuberculosis. These evasion tactics involve thwarting lysosome formation, manipulating intracellular pH, and disrupting apoptosis and autophagy processes within host cells. Specifically, MTB interferes with lysosome acidification by modulating calcium ions (Ca2+), iron ions, and hydrogen ions (H+ ), creating an optimal environment for its survival within host cells. Furthermore, MTB inhibits host cell apoptosis and autophagy, critical defense mechanisms against intracellular pathogens. Understanding these immunological escape mechanisms is paramount for developing effective tuberculosis therapies. Future research should focus on targeting MTB evasion strategies to pave the way for innovative tuberculosis treatments. Conclusion: There is still a long road ahead of us to understand the immunological escape mechanism used by MTB. Over the past 50 years, numerous studies have looked into the immune response and the pathogenic processes of MTB.

STING dependent BAX-IRF3 signaling results in apoptosis during late-stage Coxiella burnetii infection

STING (STimulator of Interferon Genes) is a cytosolic sensor for cyclic dinucleotides (CDNs) and initiates an innate immune response upon binding to CDNs. Coxiella burnetii is a Gram-negative obligate intracellular bacterium and the causative agent of the zoonotic disease Q fever. The ability of C. burnetii to inhibit host cell death is a critical factor in disease development. Previous studies have shown that C. burnetii inhibits host cell apoptosis at early stages of infection. However, during the late-stages of infection, there is host cell lysis resulting in the release of bacteria to infect bystander cells. Thus, we investigated the role of STING during late-stages of C. burnetii infection and examined STING’s impact on host cell death. We show that the loss of STING results in higher bacterial loads and abrogates IFNβ and IL6 induction at 12 days post-infection. The absence of STING during C. burnetii infection significantly reduces apoptosis through decreased caspase-8 and -3 activation. During infection, STING activates IRF3 which interacts with BAX. BAX then translocates to the mitochondria, which is followed by mitochondrial membrane depolarization. This results in increased cytosolic mtDNA in a STING-dependent manner. The presence of increased cytosolic mtDNA results in greater cytosolic 2′-3′ cGAMP, creating a positive feedback loop and leading to further increases in STING activation and its downstream signaling. Taken together, we show that STING signaling is critical for BAX-IRF3-mediated mitochondria-induced apoptosis during late-stage C. burnetii infection.

Cell death induction facilitates egress of Coxiella burnetii from infected host cells at late stages of infection.

Intracellular bacteria have evolved mechanisms to invade host cells, establish an intracellular niche that allows survival and replication, produce progeny, and exit the host cell after completion of the replication cycle to infect new target cells. Bacteria exit their host cell by (i) initiation of apoptosis, (ii) lytic cell death, and (iii) exocytosis. While bacterial egress is essential for bacterial spreading and, thus, pathogenesis, we currently lack information about egress mechanisms for the obligate intracellular pathogen C. burnetii, the causative agent of the zoonosis Q fever. Here, we demonstrate that C. burnetii inhibits host cell apoptosis early during infection, but induces and/or increases apoptosis at later stages of infection. Only at later stages of infection did we observe C. burnetii egress, which depends on previously established large bacteria-filled vacuoles and a functional intrinsic apoptotic cascade. The released bacteria are not enclosed by a host cell membrane and can infect and replicate in new target cells. In summary, our data argue that C. burnetii egress in a non-synchronous way at late stages of infection. Apoptosis-induction is important for C. burnetii egress, but other pathways most likely contribute.

Overexpression of Eimeria tenella Rhoptry Kinase 2 Induces Early Production of Schizonts.

Eimeria tenella is an obligate intracellular parasite responsible for avian coccidiosis. Like other apicomplexan parasites, such as Toxoplasma gondii, cell invasion and intracellular development rely on apical organelle content discharge, named micronemes and rhoptries. Some rhoptry (ROP) kinases (ROPK) are key virulence factors in T. gondii. To date, among the 28 ropk genes carried by E. tenella, only two to four were confirmed by proteomic analysis or immunostaining to be expressed at the sporozoite stage. We have previously shown that EtROP1 is implicated in the inhibition of host cell apoptosis by interacting with the cellular p53. This work functionally described the second ROP kinase expressed at the sporozoite stage in E. tenella. EtROP2 is an active kinase that phosphorylates cell substrates of approximately 50 kDa. Its overexpression leads to the shortening of the prepatent period and to the early development of first-generation schizonts. Conduction of RNA sequencing analysis and reverse transcriptase quantitative PCR (RT-qPCR) on the host cell allowed us to identify the mitogen-activated protein kinase (MAPK) pathway and the transcription factor cFos to be upregulated by EtROP2. We also showed by immunofluorescence assay that the active kinase EtROP2 is implicated in the p38 MAPK pathway activation. We established here that EtROP2 activates the p38 MAPK pathway through a direct or indirect phosphorylation, leading to the overexpression of the master transcription factor cFos known to be implicated in E. tenella development. IMPORTANCE Rhoptries are specialized secretory organelles found in zoite stages of apicomplexan parasites. In addition to well-conserved rhoptry neck proteins, their protein consists mostly of kinase proteins, highly divergent from eukaryotic kinases. Some of those kinases are described as major virulence factors in Toxoplasma gondii, secreted into the host cell to hijack signaling pathways. Most of those kinases remain to be characterized in Eimeria tenella. Deciphering their cellular function is a prerequisite to supporting their relevance as a druggable target in development of new means of Eimeria tenella control. Secreted divergent kinases that interact with host cell partners to modulate pathways are good candidates, as they coevolve with their host targets to ensure their function within the host and are less prone to mutations that would lead to drug resistance. The absence of any orthologous kinase in host cells makes these parasite kinases a promising drug target candidate.

HPV upregulates MARCHF8 ubiquitin ligase and inhibits apoptosis by degrading the death receptors in head and neck cancer.

The membrane-associated RING-CH-type finger ubiquitin ligase MARCHF8 is a human homolog of the viral ubiquitin ligases Kaposi's sarcoma herpesvirus K3 and K5 that promote host immune evasion. Previous studies have shown that MARCHF8 ubiquitinates several immune receptors, such as the major histocompatibility complex II and CD86. While human papillomavirus (HPV) does not encode any ubiquitin ligase, the viral oncoproteins E6 and E7 are known to regulate host ubiquitin ligases. Here, we report that MARCHF8 expression is upregulated in HPV-positive head and neck cancer (HNC) patients but not in HPV-negative HNC patients compared to normal individuals. The MARCHF8 promoter is highly activated by HPV oncoprotein E6-induced MYC/MAX transcriptional activation. The knockdown of MARCHF8 expression in human HPV-positive HNC cells restores cell surface expression of the tumor necrosis factor receptor superfamily (TNFRSF) death receptors, FAS, TRAIL-R1, and TRAIL-R2, and enhances apoptosis. MARCHF8 protein directly interacts with and ubiquitinates the TNFRSF death receptors. Further, MARCHF8 knockout in mouse oral cancer cells expressing HPV16 E6 and E7 augments cancer cell apoptosis and suppresses tumor growth in vivo. Our findings suggest that HPV inhibits host cell apoptosis by upregulating MARCHF8 and degrading TNFRSF death receptors in HPV-positive HNC cells.

Chlamydia trachomatis inhibits apoptosis in infected cells by targeting the pro-apoptotic proteins Bax and Bak

Apoptosis acts in defense against microbial infection, and many infectious agents have developed strategies to inhibit host cell apoptosis. The human pathogen Chlamydia trachomatis (Ctr) is an obligate intracellular bacterium that strongly inhibits mitochondrial apoptosis of its human host cell but there is no agreement how the bacteria achieve this. We here provide a molecular analysis of chlamydial apoptosis-inhibition in infected human cells and demonstrate that the block of apoptosis occurs during the activation of the effectors of mitochondrial apoptosis, Bak and Bax. We use small-molecule Bcl-2-family inhibitors and gene targeting to show that previous models cannot explain the anti-apoptotic effect of chlamydial infection. Although the anti-apoptotic Bcl-2-family protein Mcl-1 was strongly upregulated upon infection, Mcl-1-deficient cells and cells where Mcl-1 was pharmacologically inactivated were still protected. Ctr-infection could inhibit both Bax- and Bak-induced apoptosis. Apoptotic Bax-oligomerization and association with the outer mitochondrial membrane was reduced upon chlamydial infection. Infection further inhibited apoptosis induced conformational changes of Bak, as evidenced by changes to protease sensitivity, oligomerization and release from the mitochondrial porin VDAC2. Mitochondria isolated from Ctr-infected cells were protected against the pro-apoptotic Bcl-2-family proteins Bim and tBid but this protection was lost upon protease digestion. However, the protective effect of Ctr-infection was reduced in cells lacking the Bax/Bak-regulator VDAC2. We further found that OmpA, a porin of the outer membrane of Ctr, associated upon experimental expression with mitochondria and inhibited apoptosis, phenocopying the effect of the infection. These results identify a novel way of apoptosis inhibition, involving only the most downstream modulator of mitochondrial apoptosis and suggest that Chlamydia has a protein dedicated to the inhibition of apoptosis to secure its survival in human cells.

Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus.

Numerous large DNA viruses have evolved sophisticated countermeasures to hijack the premature programmed cell death of host cells post-infection, including the expression of proteins homologous in sequence, structure, or function to cellular Bcl-2 proteins. Kaposi sarcoma herpes virus (KSHV), a member of the gammaherpesvirinae, has been shown to encode for KsBcl-2, a potent inhibitor of Bcl-2 mediated apoptosis. KsBcl-2 acts by directly engaging host pro-apoptotic Bcl-2 proteins including Bak, Bax and Bok, the BH3-only proteins; Bim, Bid, Bik, Hrk, Noxa and Puma. Here we determined the crystal structures of KsBcl-2 bound to the BH3 motif of pro-apoptotic proteins Bid and Puma. The structures reveal that KsBcl-2 engages pro-apoptotic BH3 motif peptides using the canonical ligand binding groove. Thus, the presence of the readily identifiable conserved BH1 motif sequence “NWGR” of KsBcl-2, as well as highly conserved Arg residue (R86) forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that mimics the canonical ionic interaction seen in host Bcl-2:BH3 motif complexes. These findings provide a structural basis for KSHV mediated inhibition of host cell apoptosis and reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways.

LncRNA ZEB1-AS1/miR-1224-5p / MAP4K4 axis regulates mitochondria-mediated HeLa cell apoptosis in persistent Chlamydia trachomatis infection

ABSTRACT Persistent infection of Chlamydia trachomatis is thought to be responsible for the debilitating sequelae of blinding trachoma and infertility. Inhibition of host cell apoptosis is a persistent C. trachomatis infection mechanism. ZEB1-AS1 is a long non-coding RNA (lncRNA), which was up-regulated in persistent C. trachomatis infection in our previous work. In this study, we investigated the role of ZEB1-AS1 in persistent infection and the potential mechanisms. The results showed that ZEB1-AS1 was involved in the regulation of apoptosis, and targeted silencing of ZEB1-AS1 could increase the apoptosis rate of persistently infected cells. Mechanically, interference ZEB1-AS1 caused an apparent down-regulation of the Bcl-2/Bax ratio and the repression of the mitochondrial membrane potential with the remarkable release of cytochrome c, resulting in the significant elevation level of caspase-3 activation. Meanwhile, the luciferase reporter assay confirmed that ZEB1-AS1 acted as a sponge for miR-1224-5p to target MAP4K4. The regulatory effect of miR-1224-5p/MAP4K4 on persistent infection-induced antiapoptosis was regulated by ZEB1-AS1. In addition, ZEB1-AS1 inhibited the apoptosis of Chlamydia-infected cells by activating the MAPK/ERK pathway. In conclusion, we found a new molecular mechanism that the ZEB1-AS1/miR-1224-5p/MAP4K4 axis contributes to apoptosis resistance in persistent C. trachomatis infection. This work may help understand the pathogenic mechanisms of persistent C. trachomatis infection and reveal a potential therapeutic strategy for its treatment.

The Coxiella burnetii T4SS effector protein AnkG hijacks the 7SK small nuclear ribonucleoprotein complex for reprogramming host cell transcription.

Inhibition of host cell apoptosis is crucial for survival and replication of several intracellular bacterial pathogens. To interfere with apoptotic pathways, some pathogens use specialized secretion systems to inject bacterial effector proteins into the host cell cytosol. One of these pathogens is the obligate intracellular bacterium Coxiella burnetii, the etiological agent of the zoonotic disease Q fever. In this study, we analyzed the molecular activity of the anti-apoptotic T4SS effector protein AnkG (CBU0781) to understand how C. burnetii manipulates host cell viability. We demonstrate by co- and RNA-immunoprecipitation that AnkG binds to the host cell DExD box RNA helicase 21 (DDX21) as well as to the host cell 7SK small nuclear ribonucleoprotein (7SK snRNP) complex, an important regulator of the positive transcription elongation factor b (P-TEFb). The co-immunoprecipitation of AnkG with DDX21 is probably mediated by salt bridges and is independent of AnkG-7SK snRNP binding, and vice versa. It is known that DDX21 facilitates the release of P-TEFb from the 7SK snRNP complex. Consistent with the documented function of released P-TEFb in RNA Pol II pause release, RNA sequencing experiments confirmed AnkG-mediated transcriptional reprogramming and showed that expression of genes involved in apoptosis, trafficking, and transcription are influenced by AnkG. Importantly, DDX21 and P-TEFb are both essential for AnkG-mediated inhibition of host cell apoptosis, emphasizing the significance of the interaction of AnkG with both, the DDX21 protein and the 7SK RNA. In line with a critical function of AnkG in pathogenesis, the AnkG deletion C. burnetii strain was severely affected in its ability to inhibit host cell apoptosis and to generate a replicative C. burnetii-containing vacuole. In conclusion, the interference with the activity of regulatory host cell RNAs mediated by a bacterial effector protein represent a novel mechanism through which C. burnetii modulates host cell transcription, thereby enhancing permissiveness to bacterial infection.

Chlamydia trachomatis induces lncRNA MIAT upregulation to regulate mitochondria-mediated host cell apoptosis and chlamydial development.

Chlamydia trachomatis persistent infection is the leading cause of male prostatitis and female genital tract diseases. Inhibition of host cell apoptosis is the key to maintaining Chlamydia survival in vivo, and long noncoding RNAs (lncRNAs) play important roles in its developmental cycle and pathogenesis. However, it is not clear how lncRNAs regulate persistent Chlamydia infection. Here, using a microarray method, we identified 1718 lncRNAs and 1741 mRNAs differentially expressed in IFN‐γ‐induced persistent C. trachomatis infection. Subsequently, 10 upregulated and 5 downregulated differentially expressed lncRNAs were verified by qRT–PCR to confirm the reliability of the chip data. The GO and KEGG analyses revealed that differentially regulated transcripts were predominantly involved in various signalling pathways related to host immunity and apoptosis response. Targeted silencing of three lncRNAs (MIAT, ZEB1‐AS1 and IRF1) resulted in increased apoptosis rates. Furthermore, interference with lncRNA MIAT caused not only an obvious downregulation of the Bcl‐2/Bax ratio but also a marked release of cytochrome c, resulting in a significantly elevated level of caspase‐3 activation. Meanwhile, MIAT was involved in the regulation of chlamydial development during the persistent infection. Collectively, these observations shed light on the enormous complex lncRNA regulatory networks involved in mitochondria‐mediated host cell apoptosis and the growth and development of C. trachomatis.

Structural Investigation of Orf Virus Bcl-2 Homolog ORFV125 Interactions with BH3-Motifs from BH3-Only Proteins Puma and Hrk.

Numerous viruses have evolved sophisticated countermeasures to hijack the early programmed cell death of host cells in response to infection, including the use of proteins homologous in sequence or structure to Bcl-2. Orf virus, a member of the parapoxviridae, encodes for the Bcl-2 homolog ORFV125, a potent inhibitor of Bcl-2-mediated apoptosis in the host. ORFV125 acts by directly engaging host proapoptotic Bcl-2 proteins including Bak and Bax as well as the BH3-only proteins Hrk and Puma. Here, we determined the crystal structures of ORFV125 bound to the BH3 motif of proapoptotic proteins Puma and Hrk. The structures reveal that ORFV125 engages proapoptotic BH3 motif peptides using the canonical ligand binding groove. An Arg located in the structurally equivalent BH1 region of ORFV125 forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that mimics the canonical ionic interaction seen in host Bcl-2:BH3 motif complexes. These findings provide a structural basis for Orf virus-mediated inhibition of host cell apoptosis and reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways.

Leishmania: manipulation of signaling pathways to inhibit host cell apoptosis.

The maintenance of homeostasis in living systems requires the elimination of unwanted cells which is performed, among other mechanisms, by type I cell death or apoptosis. This type of programmed cell death involves several morphological changes such as cytoplasm shrinkage, chromatin condensation (pyknosis), nuclear fragmentation (karyorrhexis), and plasma membrane blebbing that culminate with the formation of apoptotic bodies. In addition to the maintenance of homeostasis, apoptosis also represents an important defense mechanism for cells against intracellular microorganisms. In counterpart, diverse intracellular pathogens have developed a wide array of strategies to evade apoptosis and persist inside cells. These strategies include the manipulation of signaling pathways involved in the inhibition of apoptosis where mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) play a key role. Leishmania is an intracellular protozoan parasite that causes a wide spectrum of diseases known as leishmaniasis. This parasite displays different strategies, including apoptosis inhibition, to down-regulate host cell defense mechanisms in order to perpetuate infection.

Crystal structures of ORFV125 provide insight into orf virus-mediated inhibition of apoptosis.

Premature apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Orf virus (ORFV) is a large double-stranded DNA virus belonging to the poxviridae. ORFV encodes for an apoptosis inhibitory protein ORFV125 homologous to B-cell lymphoma 2 or Bcl-2 family proteins, which has been shown to inhibit host cell encoded pro-apoptotic Bcl-2 proteins. However, the structural basis of apoptosis inhibition by ORFV125 remains to be clarified. We show that ORFV125 is able to bind to a range of peptides spanning the BH3 motif of human pro-apoptotic Bcl-2 proteins including Bax, Bak, Puma and Hrk with modest to weak affinity. We then determined the crystal structures of ORFV125 alone as well as bound to the highest affinity ligand Bax BH3 motif. ORFV125 adopts a globular Bcl-2 fold comprising 7 α-helices, and utilizes the canonical Bcl-2 binding groove to engage pro-apoptotic host cell Bcl-2 proteins. In contrast with a previously predicted structure, ORFV125 adopts a domain-swapped dimeric topology, where the α1 helix from one protomer is swapped into a neighbouring unit. Furthermore, ORFV125 differs from the conserved architecture of the Bcl-2 binding groove and instead of α3 helix forming one of the binding groove walls, ORFV125 utilizes an extended α2 helix that comprises the equivalent region of helix α3. This results in a subtle variation of previously observed dimeric Bcl-2 architectures in other poxvirus and human encoded Bcl-2 proteins. Overall, our results provide a structural and mechanistic basis for orf virus-mediated inhibition of host cell apoptosis.

The anti-apoptotic Coxiella burnetii effector protein AnkG is a strain specific virulence factor

The ability to inhibit host cell apoptosis is important for the intracellular replication of the obligate intracellular pathogen Coxiella burnetii, as it allows the completion of the lengthy bacterial replication cycle. Effector proteins injected into the host cell by the C. burnetii type IVB secretion system (T4BSS) are required for the inhibition of host cell apoptosis. AnkG is one of these anti-apoptotic effector proteins. The inhibitory effect of AnkG requires its nuclear localization, which depends on p32-dependent intracellular trafficking and importin-α1-mediated nuclear entry of AnkG. Here, we compared the sequences of ankG from 37 C. burnetii isolates and classified them in three groups based on the predicted protein size. The comparison of the three different groups allowed us to identify the first 28 amino acids as essential and sufficient for the anti-apoptotic activity of AnkG. Importantly, only the full-length protein from the first group is a bona fide effector protein injected into host cells during infection and has anti-apoptotic activity. Finally, using the Galleria mellonella infection model, we observed that AnkG from the first group has the ability to attenuate pathology during in vivo infection, as it allows survival of the larvae despite bacterial replication.

Effects of the PI3K/Akt signaling pathway on the apoptosis of early host cells infected with Eimeria tenella.

This study investigated the role of PI3K/Akt signaling pathway on host cell apoptosis in the early infection of Eimeria tenella. Chicken cecal epithelial cells were treated with apoptosis-inducer Actinomycin D (Act D) or PI3K/Akt signaling pathway inhibitor LY294002 and then infected with E. tenella. Results demonstrated that the E. tenella-infected group had less apoptosis 4-8h after the infection and more apoptosis 12-20h after the infection than the control group. At 4-20h after the infection, the apoptotic/necrotic rate and the Caspase-3 activity in the Act D + E. tenella group were lower (P < 0.01) than those in the Act D-treated group. The p-Akt and NF-κB contents in the E. tenella-infected group were higher (P < 0.01) than those in the control group 4-12h after the infection. However, the bad content and the Caspase-9/3 activity were lower (P < 0.05) in the E. tenella-infected group than in the control group. Compared with the E. tenella-infected group, the LY294002 + E. tenella group showed decreased p-Akt content and increased apoptotic/necrotic rate, bad content, NF-κB expression, membrane permeability transition pore (MPTP) openness, and Caspase-9/3 activity. Thus, the early development of E. tenella could inhibit host cell apoptosis by downregulating the Caspase-3 activity. Upregulating this activity promoted apoptosis. In addition, activating the PI3K/Akt signaling pathway inhibited the apoptosis of E. tenella host cells in the early infection by reducing the expression of the bad content, limiting the MPTP opening, and decreasing the Caspase-9 and Caspase-3 activities.

Comparison of the host cells apoptosis induced by precocious strains and virulent strains of Eimeria tenella

The present study aims to investigate the similarities and differences between the host cells apoptosis induced by virulent line of Eimeria tenella (Tsx) and precocious line (PTsx), which can provide a theoretical basis for the study of drugs and vaccines against coccidiosis. HE staining, Hoechst 33342/AnnexinV-FITC/PI composite staining, and ELISA were used to detect the infection rate, apoptosis rate, and Caspase-3 enzyme activity of host cells infected by PTsx or Tsx, respectively. The apoptotic rates and Caspase-3 absorbance of the inoculation groups were lower (P < 0.05 or P < 0.01) than those of the control group at 4h, whereas the apoptotic rates and Caspase-3 absorbance of the inoculation groups were higher (P < 0.05 or P < 0.01) than those of the control groups at 24 to 120h. At the same inoculation dose, there was no significant difference in the infection rate, apoptosis rate or Caspase-3 absorbance between Tsx groups and PTsx groups after E. tenella inoculation for 4 to 72h (P > 0.05). However, these indicators of PTsx groups were lower (P < 0.01) than those of the same dose inoculated Tsx groups at 120h. The apoptosis rates of cecal and glandular epithelial cells in the inoculated groups were higher (P < 0.01) than those in the control group after inoculated E. tenella 5 D in vivo, and the apoptosis rates of cecal and glandular epithelial cells in PTsx group was lower (P < 0.01) than that in the same dose inoculated Tsx group. These observations indicate that both Tsx and PTsx inhibit host cell apoptosis in the early development of E. tenella, induce host cell apoptosis in the middle and late stages, and the apoptosis-inducing effect on host cells increases with increasing dose. However, when the same dose of oocysts was inoculated, the amount of apoptosis induced by PTsx in late development was less than Tsx.

Apoptosis: Dual Role in Aetiology and Cure

Apoptosis is a programmed cell death which occurs following a variety of stimuli. Physiologically the process is important for morphogenesis of organs and homeostasis of different types of cells. Apoptotic cell death is responsible for a variety of pathologic states such as elimination of cell death in mutated cells, infected cells, tumour cells and transplant rejection well as the pathological atrophy. In this review, there is discussion about the control of apoptosis, detection methods of apoptosis, its association with infectious and non-communicable diseases. Intracellular microorganisms survive through inhibition of host cell apoptosis as well as they destroy the parenchymal cells causing impaired functions. It plays important role in tumourigenesis. There are possible therapeutic roles of drugs that modify apoptosis in human diseases.

Chlamydia and Its Many Ways of Escaping the Host Immune System.

The increasing number of new cases of Chlamydia infection worldwide may be attributed to the pathogen's ability to evade various host immune responses. Summarized here are means of evasion utilized by Chlamydia enabling survival in a hostile host environment. The pathogen's persistence involves a myriad of molecular interactions manifested in a variety of ways, e.g., formation of membranous intracytoplasmic inclusions and cytokine-induced amino acid synthesis, paralysis of phagocytic neutrophils, evasion of phagocytosis, inhibition of host cell apoptosis, suppression of antigen presentation, and induced expression of a check point inhibitor of programmed host cell death. Future studies could focus on the targeting of these molecules associated with immune evasion, thus limiting the spread and tissue damage caused by this pathogen.

Eimeria tenella ROP kinase EtROP1 induces G0/G1 cell cycle arrest and inhibits host cell apoptosis.

Coccidia are obligate intracellular protozoan parasites responsible for human and veterinary diseases. Eimeria tenella, the aetiologic agent of caecal coccidiosis, is a major pathogen of chickens. In Toxoplasma gondii, some kinases from the rhoptry compartment (ROP) are key virulence factors. ROP kinases hijack and modulate many cellular functions and pathways, allowing T. gondii survival and development. E. tenella's kinome comprises 28 putative members of the ROP kinase family; most of them are predicted, as pseudokinases and their functions have never been characterised. One of the predicted kinase, EtROP1, was identified in the rhoptry proteome of E. tenella sporozoites. Here, we demonstrated that EtROP1 is active, and the N‐terminal extension is necessary for its catalytic kinase activity. Ectopic expression of EtROP1 followed by co‐immunoprecipitation identified cellular p53 as EtROP1 partner. Further characterisation confirmed the interaction and the phosphorylation of p53 by EtROP1. E. tenella infection or overexpression of EtROP1 resulted both in inhibition of host cell apoptosis and G0/G1 cell cycle arrest. This work functionally described the first ROP kinase from E. tenella and its noncanonical structure. Our study provides the first mechanistic insight into host cell apoptosis inhibition by E. tenella. EtROP1 appears as a new candidate for coccidiosis control.