Metabolic reprogramming of immune cells in the battle against intracellular bacterial chronic infections: novel mechanisms and breakthroughs.

Migraine which is a mode of a headache affects all age groups and both genders with big varieties. It is treated symptomatically and plaintively in the most majority of the standard treatment all over the world. According to my work on the biological bases of the surgical pathologies for the last twenty years I noticed and analyzed the possibly of migraine could be a complication to the chronic inflammation of the skull base Para-nasal air sinuses. The modalities of migraine are related to the involved air sinus/es and to the nature of its/their affection. Chronic sinusitis in turn is a complication to a known chronic active intracellular bacterial systemic infection. This vision is gone with the trial treatment for that last twenty years all put on strict clinical analysis and clinical trial treatment directed to the systemic infection in question which is a chronic brucellosis in my career. Recently PCR open tissue biopsy admitted in to the work up of the patient which supported this view to average of 40% in a face of nearly a hundred percent successful trial treatment without any modality of palliative treatment, this involved hundred of patients with the widest range of migraine affection.

The phylogenetic tree segregates into three major groups, which probably descended from a common ancestor: the bacteria, the archaea, and the eucarya (1–3). While bacteria and archaea lack a true nucleus and intracellular organelles, eucarya possess these. The origin of the ancestor remains elusive, but it emerged about 4 billion years ago. The bacteria probably started life 3.5 billion years ago and eukaryotes emerged 1.75 billion years thereafter. Sometime in between archaea appeared. Eukaryotes began as unicellular organisms but soon also developed multicellular forms. Bacteria and archaea had sufficient time to exploit all niches of the abiotic environment, ranging from ice cold glacial lakes to fiery geysers – from the highest mountain peaks to the deepest sea beds. They also quickly developed forms of mutualism by forming colonies composed of mixed populations. With the evolution of eucarya, new environments could be exploited. Today prokaryotes are the most prevalent form of life on earth, making up the majority of our biomass. It has been estimated that more than 10 prokaryotic organisms live on our globe. Thus, archaea and bacteria are far more prevalent than eucarya. Even human beings comprise more prokaryotic cells than mammalian cells, which range on the order of 10 human cells and 10 prokaryotes mostly concentrated in our intestinal system (4–7).

Recent advancement, immune responses, and mechanism of action of various vaccines against intracellular bacterial infections

Type I interferons represent a unique and complex group of cytokines, serving many purposes during innate and adaptive immunity. Discovered in the context of viral infections, type I IFNs are now known to have myriad effects in infectious and autoimmune disease settings. Type I IFN signaling during bacterial infections is dependent on many factors including whether the infecting bacterium is intracellular or extracellular, as different signaling pathways are activated. As such, the repercussions of type I IFN induction can positively or negatively impact the disease outcome. This review focuses on type I IFN induction and downstream consequences during infection with the following intracellular bacteria: Chlamydia trachomatis, Listeria monocytogenes, Mycobacterium tuberculosis, Salmonella enterica serovar Typhimurium, Francisella tularensis, Brucella abortus, Legionella pneumophila, and Coxiella burnetii. Intracellular bacterial infections are unique because the bacteria must avoid, circumvent, and even co-opt microbial “sensing” mechanisms in order to reside and replicate within a host cell. Furthermore, life inside a host cell makes intracellular bacteria more difficult to target with antibiotics. Because type I IFNs are important immune effectors, modulating this pathway may improve disease outcomes. But first, it is critical to understand the context-dependent effects of the type I IFN pathway in intracellular bacterial infections.

Extracellular vesicles enhance the efficacy of ceftiofur against intracellular bacterial infections

Antimicrobial peptides (AMPs) selectively recognize and destroy microorganisms and, unlike conventional antibiotics, have a unique advantage in terms of harmlessness to host cells. AMPs are characterized by cationic properties and amphiphilicity, which facilitates their interaction with microbial membranes. The crucial role of AMPs in resolving infections is based on two main mechanisms: direct destruction of pathogens and immune modulation. AMPs expand their therapeutic potential through adaptive immunity. Finally, by enhancing both innate and adaptive immunity, AMPs facilitate pathogen elimination through destroy microbial membranes, lysis of foreign cells via promoting the activation of T- and B-lymphocytes, neutrophils and macrophages stimulation. Due to their diverse modes of action/multitasking, AMPs demonstrate a reduced likelihood of developing resistance to them. Since the most difficult infections to treat are intracellular bacterial infections, where antibiotics are virtually ineffective, AMPs are becoming a promising alternative for treatment. In summary, one and the same AMP can express itself in multiple structural and functional forms, which increases their adaptability and effectiveness against various microbial attacks. Antimicrobial peptides (AMPs) are essential components of immune system, capable of selectively recognizing and eliminating microorganisms that inhabit the host body. Unlike conventional antibiotics, AMPs offer a unique advantage in targeting pathogens without causing harm to host cells. These short peptides, typically ranging from 12 to 50 amino acids, are characterized by their cationic properties due to an abundance of positively charged amino acids. This enables them to exhibit amphiphilic behavior, with both hydrophilic and hydrophobic regions that facilitate interactions with microbial membranes. AMPs are critical not only for their bactericidal properties but also for their ability to modulate immune responses, thus enhancing both innate and adaptive immunity. AMPs play a pivotal role in the resolution of infections through two primary mechanisms: direct pathogen killing and immune modulation. They accomplish the former by disrupting microbial membranes, leading to cell lysis, while the latter involves the stimulation of immune cells such as neutrophils and macrophages, which amplify inflammation and accelerate pathogen clearance. Recent studies have revealed that AMPs also influence adaptive immunity, facilitating the activation of T and B-lymphocytes, thereby expanding their therapeutic potential. Importantly, AMPs exhibit a reduced likelihood of resistance development due to their diverse and simultaneous modes of action. One of the most challenging infections to treat is intracellular bacterial infections, where pathogens replicate within host cells. Antibiotics often fail in these cases due to their limited ability to penetrate host cells and the growing issue of antibiotic resistance, which prevents the therapeutic concentrations of antibiotics from reaching effective levels within the infected cells. Consequently, these infections can persist and become chronic, evading standard antibiotic treatment. In contrast, AMPs are emerging as a promising alternative for managing intracellular infections. In summary, the same AMP can exhibit multiple structural and functional properties, demonstrating a high degree of versatility. These overlapping characteristics often enhance their adaptability and efficacy against diverse microbial threats.

Gold nanoclusters treat intracellular bacterial infections: Eliminating phagocytic pathogens and regulating cellular immune response

Intracellular bacterial infections caused by antibiotic-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), pose an intractable threat to public health. Intracellular MRSA is extremely difficult to eradicate using traditional antibiotics due to the poor intracellular accumulation and drug resistance. In this work, a novel multifunctional nanoantibiotic (GZNC) was constructed using MOF-derived nanozymes loaded with botanicals for synergistic treatment of intracellular antibiotic-resistant bacterial infection. The nanoantibiotic integrated glycyrrhizinic acid (GA) into ZIF-8-derived nanozymes (ZNC), which achieved controlled release of GA, excellent photothermal effects and enhanced peroxidase-like (POD-like) activity under near-infrared (NIR) light irradiation. The nanoantibiotic showed excellent potential for in vivo and in vitro eradication of intracellular antibiotic-resistant bacteria. With the merits of NIR light-actuated botanicals/photothermal therapy (PTT)/chemodynamic therapy (CDT), the nanoantibiotic could synergistically eradicate intracellular antibiotic-resistant bacteria and alleviate associated infection, providing a promising and biologically safe pathway to address the intracellular antibiotic-resistant bacterial infection.

The barrier function of host cells enables intracellular bacteria to evade the lethality of the host immune system and antibiotics, thereby causing chronic and recurrent infections that seriously threaten human health. Currently, the main clinical strategy for the treatment of intracellular bacterial infections involves the use of long-term and high-dose antibiotics. However, insufficient intracellular delivery of antibiotics along with various resistance mechanisms not only weakens the efficacy of current therapies but also causes serious adverse drug reactions, further increasing the disease and economic burden. Improving the delivery efficiency, intracellular accumulation, and action time of antibiotics remains the most economical and effective way to treat intracellular bacterial infections. The rapid development of nanotechnology provides a strategy to efficiently deliver antibiotics against intracellular bacterial infections into cells. In this review, we summarize the types of common intracellular pathogens, the difficulties faced by antibiotics in the treatment of intracellular bacterial infections, and the research progress of several types of representative nanocarriers for the delivery of antibiotics against intracellular bacterial infections that have emerged in recent years. This review is expected to provide a reference for further elucidating the intracellular transport mechanism of nanocarrier-drug complexes, designing safer and more effective nanocarriers and establishing new strategies against intracellular bacterial infection.

Staphylococcus aureus is a primary pathogen responsible for causing postoperative infections as it survives and persists in host cells, including osteoblasts and macrophages. These cells then serve as reservoirs resulting in chronic infections. Most traditional antibiotics have poor effects on intracellular S.aureus because they cannot enter the cell. Herein, a cell-penetrating peptide TAT-KR-12 was derived from the trans-activating transcription (TAT) peptide and KR-12 (residues 18-29 of human cathelicidin LL-37). The TAT acts as a "trojan horse" to deliver KR-12 peptide into the cells to kill S.aureus. Moreover, effective antibacterial properties and biocompatibility were observed in vitro, demonstrating that TAT-KR-12 is effective not only in eliminating planktonic S.aureus, but also in eliminating intracellular S.aureus cells in vitro. TAT-KR-12, as with LL-37, also elicits strong anti-inflammatory activities in LPS-stimulated macrophages, as demonstrated by significant inhibition of NO, TNF-α, and IL-1β expression and secretion from LPS-stimulated RAW264.7 cells. In the subcutaneous infection mouse model of planktonic and intracellular infections, the growth of S.aureus in vivo is evidently inhibited without cytotoxicity. These results suggest that the novel antimicrobial TAT-KR-12 may prove to be an effective treatment option to overcome antibiotic resistance caused by intracellular bacterial infections.

Currently, chronic inflammatory pathology of paranasal sinuses mostly affecting maxillary antrum is one of the pressing issues for health care. Over the last two decades, a great etiological importance in inducing inflammation in paranasal sinuses was referred to bacterial intracellular infections caused by Mycoplasma and Chlamydia. In particular, Chlamydia, whose life cycle is closely linked to residence inside host cells defines them as pathogenic obligate intracellular gram-negative bacteria, whereas Mycoplasma is a membrane-associated microorganism able to self-replication and long persistence on host cellular membranes. Increased incidence of chronic pathology in paranasal sinuses associated with intracellular infection is shaped by a range of circumstances, primarily increased prevalence of immunocompromised subjects, worsened social and ecological conditions, uncontrolled and unjustified administration of available of antimicrobials and anti-septic agents, hormone preparations altering community of extracellular microbe populations (microbiocenoses), inhabiting natural biotope in the upper respiratory tract mucosa. These factors contribute to the lowering colony resistance, entrance and propagation of Chlamydia and Mycoplasma as a monoor mixed infection. Upon that, mixed variants of Chlamydia-Mycoplasma infection are characterized by development of more severe sinusitis accompanied with diverse complications in the lower respiratory tract, digestive tract, urinary and nerve system. There were examined 189 subjects for assessing epidemiologic characteristics and features of systemic and mucosal immune responses in patients with exacerbated chronic maxillary sinusitis associated with intracellular bacterial infection. Presence of intracellular bacterial infection was confirmed by laboratory tests: direct immune fluorescent analysis and PCR. It was found that high prevalence of Сhlamydia trachomatis, Chlamydophila pneumoniae and Mycoplasma pneumoniae in patients with exacerbated chronic inflammatory pathology of paranasal sinuses. Comparing laboratory test data for patients with identified intracellular bacterial pathogens vs. those with negative results revealed a common trend in pathologic immune-related changes that fits to typical host anti-infection response manifested by inflammatory process. Besides, we described features of immune reactivity in patients with verified Chlamydia infection including more pronounced unbalance in Т cell immunity as well as evelated parameters of humoral immunity in patients with verified Chlamydia and Mycoplasma infection.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains as a leading killer among infectious diseases worldwide. The nature of the host immune response dictates whether the initial Mtb infection is cleared or progresses toward active disease, and is ultimately determined by intricate host-pathogen interactions that are yet to be fully understood. The early immune response to infection is mediated by innate immune cells, including macrophages and neutrophils that can phagocytose Mtb and mount an antimicrobial response. However, Mtb can exploit these innate immune cells for its survival and dissemination. Recently, it has become clear that the immune response and metabolic remodeling are interconnected, which is highlighted by the rapid evolution of the interdisciplinary field of immunometabolism. It has been proposed that the net outcome to Mtb infection—clearance or chronic disease—is likely a result of combined immunologic and metabolic activities of the immune cells. Indeed, host cells activated by Mtb infection have strikingly different metabolic requirements than naïve/non-infected cells. Macrophages activated by Mtb-derived molecules or upon phagocytosis acquire a phenotype similar to M1 with elevated production of pro-inflammatory molecules and rely on glycolysis and pentose phosphate pathway to meet their bioenergetic and metabolic requirements. In these macrophages, oxidative phosphorylation and fatty acid oxidation are dampened. However, the non-infected/naive, M2-type macrophages are anti-inflammatory and derive their energy from oxidative phosphorylation and fatty acid oxidation. Similar metabolic adaptations also occur in other phagocytes, including dendritic cells, neutrophils upon Mtb infection. This metabolic reprogramming of innate immune cells during Mtb infection can differentially regulate their effector functions, such as the production of cytokines and chemokines, and antimicrobial response, all of which can ultimately determine the outcome of Mtb-host interactions within the granulomas. In this review, we describe key immune cells bolstering host innate response and discuss the metabolic reprogramming in these phagocytes during Mtb infection. We focused on the major phagocytes, including macrophages, dendritic cells and neutrophils and the key regulators involved in metabolic reprogramming, such as hypoxia-inducible factor-1, mammalian target of rapamycin, the cellular myelocytomatosis, peroxisome proliferator-activator receptors, sirtuins, arginases, inducible nitric acid synthase and sphingolipids.

Humoral immunity and B cell memory are essential components of the adaptive immune response. These elements of immunity have remained largely unexplored in intracellular bacterial infections. Ehrlichia muris is an obligate intracellular bacterium that generates a chronic infection in immunocompetent mice. Chronic infection with E. muris is characterized by long-term IgM production that confers antibody-mediated protection against virulent ehrlichial challenge. We have identified a novel CD19+ B cell population in the spleens of chronically infected mice based on the expression of the cell surface markers CD11c, CD73, and PD-L2. As determined by fluorescence microscopy, these cells are localized in germinal centers of the spleen. Upon stimulation with LPS in vitro, the CD11c+/CD73+/PD-L2+ B cells proliferated and produced antigen specific IgM. BrdU incorporation studies revealed that the population is largely quiescent, and new cells were not recruited to this population during chronic infection. We propose that the CD11c+/CD73+/PD-L2+ B cells we have identified during chronic infection, are long-lived effector/memory cells responsible for the maintenance of long-term immunity during chronic ehrlichial infection.

The impact of the interaction between NK cells and lung dendritic cells (LDCs) on the outcome of respiratory infections is poorly understood. In this study, we investigated the effect and mechanism of NK cells on the function of LDCs during intracellular bacterial lung infection of Chlamydia muridarum in mice. We found that the naive mice receiving LDCs from C. muridarum-infected NK-cell-depleted mice (NK-LDCs) showed more serious body weight loss, bacterial burden, and pathology upon chlamydial challenge when compared with the recipients of LDCs from infected sham-treated mice (NK+LDCs). Cytokine analysis of the local tissues of the former compared with the latter exhibited lower levels of Th1 (IFN-γ) and Th17 (IL-17), but higher levels of Th2 (IL-4), cytokines. Consistently, NK-LDCs were less efficient in directing C. muridarum-specific Th1 and Th17 responses than NK+LDCs when cocultured with CD4(+) T cells. In NK cell/LDC coculture experiments, the blockade of NKG2D receptor reduced the production of IL-12p70, IL-6, and IL-23 by LDCs. The neutralization of IFN-γ in the culture decreased the production of IL-12p70 by LDCs, whereas the blockade of TNF-α resulted in diminished IL-6 production. Our findings demonstrate that NK cells modulate LDC function to elicit Th1/Th17 immunity during intracellular bacterial infection.

Intracellular infections by Gram-negative bacteria are a significant global health threat. The nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) was recently shown to sense cytosolic bacterial lipopolysaccharide (LPS). However, the potential role for Nur77 in controlling intracellular bacterial infection has not been examined. Here we show that Nur77 protects against intracellular infection in the bladder by uropathogenic Escherichia coli (UPEC), the leading cause of urinary tract infections (UTI). Nur77 deficiency in mice promotes the formation of UPEC intracellular bacterial communities (IBCs) in the cells lining the bladder lumen, leading to persistent infection in bladder tissue. Conversely, treatment with a small-molecule Nur77 agonist, cytosporone B, inhibits invasion and enhances the expulsion of UPEC from human urothelial cells in vitro, and significantly reduces UPEC IBC formation and bladder infection in mice. Our findings reveal a new role for Nur77 in control of bacterial infection and suggest that pharmacologic agonism of Nur77 function may represent a promising antibiotic-sparing therapeutic approach for UTI.