Arrest of phagosome maturation and inhibition of Cts D conversion to active forms in infected macrophages reduced the generation and presentation of immunodominant antigen epitopes to T cells resulting in low IL-2 production Singh et al. Pathogenic species of Mycobacterium , including M.
This regulation may be accomplished by a few factors, including miRNAs. During M. In contrast, challenge with non-virulent M.
The up-regulation of miRb-5p resulted in decreased Cts S activity accompanied by increased intracellular survival of M. Down-regulation of cathepsin S activity and gene expression in human macrophages infected with mycobacteria also depends on IL production Sendide et al. Macrophages infected with M. However, these negative effects could be reversed by antibody neutralization of IL or transfection of BCG-infected macrophages with active recombinant Cts S Sendide et al.
Restoration of surface levels of MHC class II molecules in macrophages could be achieved also by infection of cells with a recombinant BCG strain engineered to express and secrete biologically active human Cts S Soualhine et al. Another reason for the impaired trafficking and intracellular retention of MHC class II molecules in BCG-infected macrophages was the intraphagosomal production of urease and subsequent alkalization of endosomes, responsible for MHC class II processing and loading Sendide et al.
Endosome alkalization therefore may not only affect the Cts S but also the activity of key proteases participating in MHC class II presentation pathway Baena and Porcelli, These alterations in Cts B by M. Interestingly, during M. Pathogenic mycobacteria may also influence the level of Cts G in macrophages.
Down-regulation of Cts G expression positively correlates with increased bacterial survival, thus creating an immune evasion mechanism for M. Similarly, in vivo infection of alveolar macrophages with non-virulent M. However, Cts G-deficient mice could not eliminate M. Neutrophils are the main population of professional phagocytes responsible for delivery of Cts G into the bronchoalveolar space of M. It is suggested that Cts G and other proteolytic enzymes may be shuttled into mycobacteria-infected alveolar macrophages together with phagocytosed apoptotic neutrophils Steinwede et al.
Within macrophages, phagocytosed neutrophil with their granule contents are then transported to the early endosomes and colocalize with mycobacteria, promoting the antimycobacterial activity of macrophages and facilitating the killing of M. The bacterial protein Rvc, secreted by infected macrophages, binds to and inhibits activity of membrane Cts G leading to suppression of activation of caspasedependent apoptosis Danelishvili et al.
A recent report shows that Cts X, in the presence of the nitric oxide NO , is involved in rapid killing of pathogenic Mycobacterium avium subsp. This pathogen primarily infects the urogenital tract; however, it may spread from the local site of infection contributing to development of pelvic inflammatory disease, endocarditis, arthritis and dermatitis. Gonococcal infection is characterized by a local inflammatory response driven by a large number of neutrophils and macrophages, especially during acute gonorrhea.
Therefore, modulation of Cts B activity may represent an important bacterial mechanism involved in regulation of inflammatory response and pathogenesis of infections caused by N.
Cts B targets bacterial penicillin-binding protein 2 PBP2 , which is an essential peptidoglycan transpeptidase engaged in cell division Shafer et al. On the other hand, lysosomal serine Cts G can directly kill N. It does so by degrading porin and colony opacity-associated proteins Opa in the N.
Opa-expressing N. However, bacterial exposure to Cts G resulted in a comparable dose-dependent killing of both Opa-expressing and Opa-deficient strains. The increased susceptibility of Opa-expressing gonococci to neutrophil killing is mediated by CEACAM-dependent triggering of Src family kinase signaling, which promote bacteria trafficking into mature, degradative phagolysosomes where the bacteria are exposed to components with antigonococcal activity, including bactericidal-permeability-increasing protein BPI Johnson et al.
It is responsible for listeriosis, affecting mainly pregnant women, their fetuses, and immunocompromised individuals, causing meningoencephalitis, meningitis, septicemia, and brain abscess Farber and Peterkin, Macrophages are generally thought to be the major population of phagocytes responsible for intracellular elimination of L.
Cts D expression increases in macrophages infected with L. RAW The molecular mechanism by which Cts D influences L. Therefore, lysosomal and soluble active Cts D forms that are present abundantly in bacteria phagosomes can cleave LLO monomers and participate in intraphagosomal killing of L.
In addition to Cts D, also Cts G, derived from human neutrophils, can destroy Listeria in in vitro conditions Alford et al.
Methicillin-resistant S. Macrophages are the major cells responsible for clearance of bacteria from infected tissues, however S. After phagocytosis, the S. Additionally, USA strain persisted and replicated within the phagosome, and the acidification of this compartment was necessary for bacteria survival. This indicates that live S. In in vitro experimental models such as RAW The pathogen is degraded in Cts D-positive active lysosomes in primary human macrophages, but still the majority of bacteria survive in late phagosomes Brann et al.
During S. This impaired phagolysosomal biogenesis in COMMDdeficient cells favors the survival of bacteria within macrophages Shlomo et al. In cell types other than macrophages, e.
For instance, Cts C contributes to indirect killing of S. Neutrophil-derived Cts G has limited and delayed bactericidal effect, because S. This pathogen replicates predominantly in macrophages, but can proliferate in other cell types too Pechous et al. Four subspecies of F. Following uptake by macrophages, F. Late endosomal Francisella -containing vacuole FCV disintegrates within a few hours allowing the pathogen to escape into the cytoplasm, where it replicates.
Interestingly, T cells from vaccinated mice can provide a functional assistance in arresting Francisella attenuated live vaccine strain LVS replication and inhibiting the spread of LVS infection between macrophages in in vitro conditions. Pathomechanisms of tularemia infection have best been studied in mice and rabbits. Removal of Cts B in mice rendered them resistant to infection with F.
Measured at 3 day after infection, Cts B-knockout animals produced less pro-inflammatory cytokines and chemokines in the liver Qi et al.
Macrophages are the frontline in controlling intracellular growth and dissemination of Francisella Hall et al. Interestingly, cell structure analysis by transmission electron microscopy revealed that uninfected macrophages lacking cathepsin B contained larger lysosomes and autophagosomes, and accumulated partially digested vesicles in autophagosomes, compared to WT cells.
Mechanistically, the increased bactericidal activity against F. This pathogen is the causative agent of brucellosis in humans and livestock.
In humans, B. Upon internalization, Brucella arrests phagosome maturation between the steps of acidification and phagosome-lysosome fusion and cannot be destroyed within the Brucella -containing vacuole BCV Rittig et al. In human macrophage-like cell line THP-1, delivery of Cts D to phagosomes occurred simultaneously with the arrival of LAMP-1 and acidification of the lumen of the phagosomes at the early stages of infection 60 min pi with virulent or HK B.
Together with the time progression, the number of Cts D-positive phagosomes containing live B. During later stages of infection, BCVs were shown to fuse with lysosomes, what is needed for further maturation of BCVs into an endoplasmic reticulum ER -derived organelle, in which bacteria is able to replicate Bellaire et al. Several virulence factors determine Brucella survival in macrophages, including zinc-dependent metalloproteinase ZnMP. Its deletion causes an increase in the co-localization of bacteria with phagosomal Cts D, reducing intracellular replication of the pathogen within RAW Importantly, B.
This cytokine suppresses lysosome-mediated killing of bacteria in macrophages via two distinct regulatory mechanisms.
Although, there are no available data concerning the influence of Brucella on cathepsin activity in macrophages and the role of these enzymes during Brucella infection, Coria et al. Additionally, U-Omp19 reduces the ability of macrophages and DCs to degrade extracellular Ag but increases the amount of Ag inside DCs due to inhibition of its intracellular proteolysis within lysosomal compartments. Shigella infection occurs particularly in young children under 5 years old and immunocompromised adults in developing countries and causes significant morbidity and mortality Kotloff et al.
Shigella crosses the intestinal epithelium by transcytosis through microfold cells M cells , reaching resident macrophages and DCs in the M cell pocket.
Bacteria can survive and replicate in macrophages, escape the phagocytic vacuole, and kill the host cell by inducing caspasedependent pyroptotic cell death, allowing subsequent invasion of epithelial cell layer Schroeder and Hilbi, ; Ashida et al. Currently, the role of cathepsins during S. The activity of Cts D in splenocytes of CBA mice infected with Shigella strains was variable in the cytoplasmic and lysosomal cell compartments and depended on the virulence of Shigella strains.
Strong and prolonged activation of Cts D was observed in both compartments after infection with virulent Shigella strains, whereas avirulent strains induced only temporary Cts D activity in the lysosomes Belaia et al. According to authors, determination of the Cts D activity in splenocytes of animals infected with Shigella allows differentiation of virulent and from avirulent strains of the pathogen.
Future studies should elucidate the major implications of cathepsins in host defense and pathogenesis of Shigella infections. Typhimurium is a pathogenic Gram-negative rod bacterium that causes foodborne salmonellosis in humans and a wide range of animal species McSorley, Infection of laboratory mice with S. Typhimurium results in disseminated infection with some similarities to human disease caused by the human-host restricted S. Therefore, S.
Typhimurium infection of mice is widely accepted as an experimental model for human disease Hilgenberg et al. Salmonella penetrates the epithelium of the small intestine following oral ingestion, and preferentially infects phagocytes, including macrophages, within lamina propria. Typhimurium can reside and replicate in macrophages Salcedo et al.
To survive in macrophages, the bacteria avoid intracellular killing by preventing lysosome fusion with the modified endosome, known as Salmonella -containing vacuole SCV Alpuche-Aranda et al.
It is likely that S. Typhimurium blocks maturation of its phagosome, because phagosomes isolated from S. Typhimurium - infected macrophages contained only pro-Cts L and not mature Cts L Mills and Finlay, , whereas Cts B activity is decreased in macrophages Sarkar et al. Acidification of SCV is necessary for bacteria virulence Arpaia et al. Typhimurium excludes active cathepsins from the SCV in primary murine macrophages Hang et al. But other studies have reported that upon initial infection of BMDMs 2 h , the cysteine cathepsins gained access to S.
Typhimurium in compartments of varied pH Sanman et al. Bacteria also induced the increase in lysosomal pH resulting in an overall decline in cysteine cathepsin activity not only in infected but also in a fraction of bystander cells, indicating a mechanism by which Salmonella can alter the functionality of nearby uninfected cells Sanman et al. Typhimurium infection, cathepsins may not directly target the bacteria but may be involved in triggering pyroptotic cell death of infected macrophages.
As reported by Selkrig et al. Nuclear cathepsins were active and had a higher molecular weight compared to their lysosomal counterparts. Nuclear cathepsin activity was responsible for pyroptosis through the non-canonical inflammasome activation Selkrig et al. Mycoplasmas are the smallest self-replicating bacteria that completely lack a cell wall. They colonize mucosal surfaces of respiratory and urogenital tracts in humans and many different animal species.
Mycoplasmas are mainly facultative intracellular organisms, however some of them are considered obligatory intracellular microorganisms Nascimento et al. Among pathogenic mycoplasma species, those of greatest clinical importance for humans are: M. In vitro and in vivo studies point to macrophages are as the major cells engaged in elimination of mycoplasma Erb and Bredt, ; Schimmelpfeng et al. It is therefore possible that cathepsin proteases may participate in elimination and control of mycoplasma infections.
Cts L-deficient mice present significantly lower percentage of macrophages and higher mycoplasma burden in lungs and exhibit more severe pneumonia, compared to WT animals, following infection with M. Cts L probably has no direct toxic effect on mycoplasma, since it alters neither bacterial viability nor growth of M. Instead, Cts L indirectly controls mycoplasma infection by promoting lymphangiogenesis and antibacterial cellular immune responses Xu et al.
Cts L can also promote mucosal immune response, which provides protection against mycoplasma pneumonia in piglets infected with M. Enhancement of mucosal response by Cts L is mediated by stimulation of sIgA secretion through efficient Ii processing and antigen presentation. Treatment of animals with rCts L before challenge with M. Interestingly, Cts L levels were higher in DC than macrophages in most tissues of piglets infected with M.
Q fever can cause acute or chronic infection, and the most frequent clinical sign of chronic Q fever is endocarditis Eldin et al. This pathogen exhibits strong tropism to mononuclear phagocytes, such as monocytes and macrophages. This secretion system allows the pathogen to translocate a large repertoire of effectors to the host cytosol, allowing the remodeling of host cell processes and the creation of a replicative niche while still maintaining the host cell homeostasis Newton et al.
Virulent and avirulent C. Virulent C. Conversely, CCV hiding avirulent C. This trafficking behavior correlates with avirulent C. However, these prior findings are contradicted by Howe et al. Another study supports the notion that lysosomal hydrolases, including Cts D, are not required for C. Specific antibodies found in chronic Q fever patients likely favor C. The large CCV containing C. Reduction of lysosomal content in C.
Additionally, HeLa cells overexpressing the transcription factor EB TFEB , which coordinates expression of lysosomal genes for lysosomal proteases and hydrolases, led to increased Cts B activity, indicating an increase in the number of proteolytically-active lysosomes. TFEB-induced lysosome biogenesis significantly reduced C. These data underscore the importance of Cts B in the control of C.
Gram-negative C. In women, it can cause cervicitis, and in both men and women the infection can lead to urethritis and proctitis. Mice inoculated with the murine pathogen C. During experimental genital infection with Chlamydia , there is recruitment of monocytes and macrophages to the genital tract which phagocytose and eliminate the pathogen intracellularly, limiting the development of disease.
However, when intracellular killing is not effective, especially in M2 macrophages, bacteria can be easily disseminated to the lymphatic system and further replicate in the draining lymph nodes Lausen et al. Cts B activity was increased in murine RAW In macrophages infected with C. Furthermore, the accumulation of active lysosomal protease Cts D within bacteria inclusions has been demonstrated in different types of C.
Accumulation of Cts D clearly preceded the decrease in transcription of preS rRNA, suggesting the involvement of this protease in bacterial death. Gram-negative rickettsiae are important causative agents of various ailments within the group of arthropod-borne diseases. Rickettsia are classified into four distinct groups based on their genome sequences, including the typhus group TG with Rickettsia typhi and Rickettsia prowazekii , the spotted fever group SFG , the ancestral group AG , and the transitional group TRG Snowden and Bhimji, Macrophages may play an important role in the pathogenesis of rickettsial diseases, because various bacteria species show some ability to proliferate within these cells depending on their virulence Curto et al.
The dichotomy regarding Rickettsia ability to survive within macrophages has been extensively documented in SPG members that cause human tick-borne diseases with varying severity Curto et al.
A pathogenic R. In THP-1 macrophages, R. Therefore, they can efficiently proliferate within THP-1 cells. In contrast, R. Overall, pathogenic and non-pathogenic SFG Rickettsia trigger differential transcriptomic and proteomic signatures in THP-1 cells, what may partially explain different intracellular fates of these pathogens within macrophages Curto et al. It should be also added that pathogenic SFG rickettsiae may possibly increase their intracellular survival within macrophages by avoidance of digestion by lysosomal enzymes, including cathepsins.
Therefore, the role of these proteases in the host response to Rickettsia infection should be elucidated in future studies. Cathepsins are undoubtedly important proteases that participate in killing various bacterial pathogens both directly or indirectly. In doing so, pathogens escape toxic bactericidal lysosomal compounds, including cathepsins, therefore, they can survive and even replicate within specialized engulfing cells, such as macrophages.
Further, certain intracellular pathogens are able to modify and exclude cathepsins from bacteria-containing vacuoles, allowing them to adapt to this hostile endolysosomal system as a niche for efficient growth. Cathepsins regulate many innate functions of macrophages including those that support adaptive immune responses that ultimately control of bacterial infections.
Consequently, bacterial pathogens manipulate expression, activity and bioavailibility of cathepsins, thus compromising their ability to kill bacteria, and ultimately leading to disease exacerbation. However, the exact mechanisms engaged by bacteria remain unclear in many cases and further investigation are warranted to better define their role in human diseases and to identify new therapeutic targets or vaccines.
Because cathepsins are enzymes they can directly digest pathogens and thus contribute to derivation of antigenic epitopes required for the generation of adaptive immunity. However, many studies summarized in this review were performed using in vitro -generated murine macrophages or leukemia-derived monocytic cell lines, which do not accurately reflect physiological conditions.
Therefore, the role of cathepsins in regulation of mechanisms of the antimicrobial immune response and pathogenesis of bacterial diseases requires further in vivo studies in animal models and humans. LS-D conceptualized the article. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We sincerely apologize to those authors whose original publications were not cited in this review due to space limitation. We would like to thank Ada, Anastazja, Konstanty Dabrowscy, and Tobiasz Turbak for their invaluable assistance during preparation of this manuscript. Abd-Elrahman I. Characterizing cathepsin activity and macrophage subtypes in excised human carotid plaques. Stroke 47, — Alam S. Alford C. Listericidal activity of human neutrophil cathepsin G. Alpuche-Aranda C.
II Salmonella stimulate macrophage macropinocytosis and persist within spacious phagosomes. Amaral E. Lysosomal cathepsin release is required for NLRP3-inflammasome activation by Mycobacterium tuberculosis in infected macrophages.
Arpaia N. TLR signaling Is required for Salmonella typhimurium virulence. Cell 5 , — Asare R. Exploitation of host cell biology and evasion of immunity by Francisella tularensis. Ashida H. Manipulation of the host cell death pathway by Shigella. Baena A. Evasion and subversion of antigen presentation by Mycobacterium tuberculosis.
Tissue Antigens 74 3 , — Bakaletz L. Phagocytosis and killing of bacteria by middle ear macrophages. Head Neck Surg. Barrett A. Google Scholar. Bastaert F.
Pseudomonas aeruginosa LasB subverts alveolar macrophage activity by interfering with bacterial killing through downregulation of innate immune defense, reactive oxygen species generation, and complement activation. Beers C. Belaia I. Cathepsin D activity in splenocytes in relation to Shigella virulence in an experiment. Bellaire B. Opsonized virulent Brucella abortus replicates within nonacidic, endoplasmic reticulum-negative, LAMPpositive phagosomes in human monocytes. Bennett K.
Antigen processing for presentation by class II major histocompatibility complex requires cleavage by cathepsin E. Benoit M. Macrophage polarization in bacterial infections.
These acts of martyrdom buy the rest of the immune system time to prepare a more targeted attack. Some innate immune cells are also just plain adorable.
Their goal in life is to chow down for the greater good. Dendritic cells have a similar modus operandi. Like macrophages, they specialize in regurgitating gunk for other immune cells. But they are much more social than macrophages, which prefer to gorge and digest in solitude. Innate immune cells might be convenient dates, for a time. The real keepers belong to the adaptive branch of the immune system: B cells—the makers of antibodies—and T cells, which, among many other tasks, kill virus-infected cells.
Adaptives are slow-moving specialists. B and T cells are self-assured enough to know what they want. But the antibodies they deploy can be powerful enough to quash microbes before they break into cells, potentially halting infections in their tracks. And even after antibodies disappear, B cells persist, ready to produce more.
Collectively known as professional phagocytes or "cells that eat" , these include cells like neutrophils and eosinophils. The mechanism that these cells use to ingest foreigners is known as phagocytosis.
This includes a more general, nonspecific response. This response doesn't require antibodies or other identifying marks. Along with this, these cells also release molecules called complement which is a sort of relay race that winds up punching holes in enemy organisms.
This initial fast and deadly response is highly variable and NK cell function is marked as much by the local milieu of hormones as the conditions of the host. As Jan Klein puts it in Immunology Blackwell Scientific Publications, : The NK cell response is influenced by a wide variety of factors such as steroids, stress-related neuropeptides, exercise, smoking, alcoholism, diet, and the pre-existing disease state. The NK cell response therefore depends to some degree on the emotional or the physiological state of the patient at the time of infection.
After this first line of defense, a set of responses that are able to identify specifically the particular trouble makers, whether it is a foreign infection or the body's own cells misbehaving e. This type of immunity is known as acquired immunity. The cells that accomplish the elimination of infection or correction in the body's functioning fall into two categories, humoral and cell-mediated types of immunity. When danger is seen, they rapidly make many copies of themselves known as clonal expansion and become effector cells.
These either help the body to clear pathogens or do the dirty work themselves of killing infected or aberrant misbehaving cells. Once the danger is past, most will commit suicide. The rest will kick back into a semi-retirement, old hands known as memory cells. These will remain vigilant for a possible reintroduction by the offending pathogen.
One of the first specific responses starts with the antigen-presenting cell APC. Such cells as macrophages, neutrophils or dendritic cells engulf and cut up an invading bacteria, virus etc. Sometimes, the pathogen is processed chewed up inside the cell and a little piece or antigen is displayed on the cell's surface.
The antigen is embedded in a molecule called the major histocompatibility complex MHC. The MHC transports the antigen to the cell's surface where it is "presented" to T-cells. At this point, the T cells are then activated to look for pathogens. This is the same molecule referred to when people have a bone marrow transplant, say, and they have to have a "matching" tissue type. Some stay outside cells extracellular. Some bacteria and fungi hang out in the spaces between cells, eating and replicating in tissues.
Others, like viruses and other bacteria, get inside cells intracellular. Viruses hijack your cell's genetic machinery to make more of themselves. The immune system has, broadly, two different arms to deal with these.
One is called humoral immunity and the other cell-mediated immunity. Humoral immunity is mobilized to arrest extracellular infections mostly. The antibodies secreted by B-cells attack these extracellular infections. Cytotoxic killer T cells: These are killer cells. They punch holes in the walls of the pathogen cell so that the contents ooze out. Dendritic cells: These cells are like the spies.
They notice if there is an invader and then present evidence of the invader to T cells in the lymph nodes. B cells: These produce antibodies, which lock onto the antigen of invading bacteria and immobilise them until the macrophage consumes them.
Some B cells become memory cells after being activated by the presence of antigen. These cells are able to live for a long time and can respond quickly following a second exposure to the same antigen.
Suppressor T cells: When the infection is gone, the immune system needs to be calmed down or the killer cells may keep killing. The suppressor T cells slow down or turn off the immune system to prevent damage to good cells. The tissues and organs involved in the immune system are the lymphatic system, lymph nodes and lymph fluid.
These all have specific functions:. When a pathogen disease-causing organism invades the body, the neutrophils gather at the entry site and try to engulf it and destroy it. Should the invaders get past the neutrophils, several things may happen.
The macrophages big eaters will be attracted by the death throes of the neutrophils. These cells attempt to engulf the invader, but they also send signals to other cells for help.
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