-
Frontiers in Immunology 2019Phagocytosis is one of the key innate defense mechanisms executed by specialized cells in multicellular animals. Recent evidence suggests that a particular phagocytic... (Review)
Review
Phagocytosis is one of the key innate defense mechanisms executed by specialized cells in multicellular animals. Recent evidence suggests that a particular phagocytic receptor expressed by human polymorphonuclear granulocytes, the carcinoembryonic antigen-related cell adhesion molecule 3 (CEACAM3), is one of the fastest-evolving human proteins. In this focused review, we will try to resolve the conundrum why a conserved process such as phagocytosis is conducted by a rapidly changing receptor. Therefore, we will first summarize the biochemical and structural details of this immunoglobulin-related glycoprotein in the context of the human CEACAM family. The function of CEACAM3 for the efficient, opsonin-independent detection and phagocytosis of highly specialized, host-restricted bacteria will be further elaborated. Taking into account the decisive role of CEACAM3 in the interaction with pathogenic bacteria, we will discuss the evolutionary trajectory of the CEACAM3 gene within the primate lineage and highlight the consequences of CEACAM3 polymorphisms in human populations. From a synopsis of these studies, CEACAM3 emerges as an important component of human innate immunity and a prominent example of a dedicated receptor for professional phagocytosis.
Topics: Animals; Bacteria; Biological Evolution; Carcinoembryonic Antigen; Humans; Immunity, Innate; Phagocytosis; Primates
PubMed: 32117212
DOI: 10.3389/fimmu.2019.03160 -
Seminars in Immunology Jun 2018Rapid elimination of microbes from the bloodstream, along with the ability to mount an adaptive immune response, are essential for optimal host-defense. Kupffer cells... (Review)
Review
Rapid elimination of microbes from the bloodstream, along with the ability to mount an adaptive immune response, are essential for optimal host-defense. Kupffer cells are strategically positioned in the liver sinusoids and efficiently capture circulating microbes from the hepatic artery and portal vein, thus preventing bacterial dissemination. In vivo and in vitro studies have probed how complement receptor of the immunoglobulin superfamily (CRIg), also referred to as Z39Ig and V-set and Ig domain-containing 4 (VSIG4), acts as a critical player in pathogen recognition and clearance. While recent data suggested that CRIg may bind bacterial cell wall components directly, the single transmembrane receptor is best known for its interaction with complement C3 opsonization products on the microbial surface. On Kupffer cells, CRIg must capture opsonized microbes against the shear forces of the blood flow. In vivo work reveals how immune adherence (IA), a process in which blood platelets or erythrocytes associate with circulating bacteria, plays a critical role in regulating pathogen capture by CRIg under flow conditions. In addition to its typical innate immune functions, CRIg was shown to directly and indirectly influence adaptive immune responses. Here, we review our current understanding of the diverse roles of CRIg in pathogen elimination, anti-microbial immunity and autoimmunity. In particular, we will explore how, through selective capturing by CRIg, an important balance is achieved between the immunological and clearance functions of liver and spleen.
Topics: Agglutination; Animals; Bacterial Infections; Complement C3; Host-Pathogen Interactions; Humans; Immunomodulation; Kupffer Cells; Opsonin Proteins; Pathogen-Associated Molecular Pattern Molecules; Receptors, Complement; Receptors, Pattern Recognition
PubMed: 29573978
DOI: 10.1016/j.smim.2018.02.007 -
Frontiers in Immunology 2023Influenza A virus infection (IAV) often leads to acute lung injury that impairs breathing and can lead to death, with disproportionate mortality in children and the...
Influenza A virus infection (IAV) often leads to acute lung injury that impairs breathing and can lead to death, with disproportionate mortality in children and the elderly. Surfactant Protein A (SP-A) is a calcium-dependent opsonin that binds a variety of pathogens to help control pulmonary infections by alveolar macrophages. Alveolar macrophages play critical roles in host resistance and susceptibility to IAV infection. The effect of SP-A on IAV infection and antiviral response of macrophages, however, is not understood. Here, we report that SP-A attenuates IAV infection in a dose-dependent manner at the level of endosomal trafficking, resulting in infection delay in a model macrophage cell line. The ability of SP-A to suppress infection was independent of its glycosylation status. Binding of SP-A to hemagglutinin did not rely on the glycosylation status or sugar binding properties of either protein. Incubation of either macrophages or IAV with SP-A slowed endocytic uptake rate of IAV. SP-A interfered with binding to cell membrane and endosomal exit of the viral genome as indicated by experiments using isolated cell membranes, an antibody recognizing a pH-sensitive conformational epitope on hemagglutinin, and microscopy. Lack of SP-A in mice enhanced IFNβ expression, viral clearance and reduced mortality from IAV infection. These findings support the idea that IAV is an opportunistic pathogen that co-opts SP-A to evade host defense by alveolar macrophages. Our study highlights novel aspects of host-pathogen interactions that may lead to better understanding of the local mechanisms that shape activation of antiviral and inflammatory responses to viral infection in the lung.
Topics: Animals; Mice; Hemagglutinins; Influenza A virus; Macrophages; Pulmonary Surfactant-Associated Protein A; Orthomyxoviridae Infections
PubMed: 36960051
DOI: 10.3389/fimmu.2023.919800 -
FEBS Letters Aug 2020The complement system is a major humoral component of immunity and is essential for the fast elimination of pathogens invading the body. In addition to its indispensable... (Review)
Review
The complement system is a major humoral component of immunity and is essential for the fast elimination of pathogens invading the body. In addition to its indispensable role in innate immunity, the complement system is also involved in pathogen clearance during the effector phase of adaptive immunity. The fastest way of killing the invader is lysis by the membrane attack complex, which is formed by the terminal components of the complement cascade. Not all pathogens are lysed however and, if opsonized by a variety of molecules, they undergo phagocytosis and disposal inside immune cells. The most important complement-derived opsonins are C1q, the first component of the classical pathway, MBL, the initiator of the lectin pathway and C3-derived activation fragments, including C3b, iC3b and C3d, which all serve as ligands for their corresponding receptors. In this review, we discuss how complement receptors are utilized by various immune cells to tackle invading microbes, or by pathogens to evade host response.
Topics: Animals; Complement Pathway, Classical; Complement Pathway, Mannose-Binding Lectin; Complement System Proteins; Host-Pathogen Interactions; Humans; Infections; Receptors, Complement
PubMed: 31989596
DOI: 10.1002/1873-3468.13743 -
Blood Advances Aug 2023Dysregulated activation of the complement system is implicated in the onset or progression of several diseases. Most clinical-stage complement inhibitors target the...
Dysregulated activation of the complement system is implicated in the onset or progression of several diseases. Most clinical-stage complement inhibitors target the inactive complement proteins present at high concentrations in plasma, which increases target-mediated drug disposition and necessitates high drug levels to sustain therapeutic inhibition. Furthermore, many efforts are aimed at inhibiting only terminal pathway activity, which leaves opsonin-mediated effector functions intact. We describe the discovery of SAR443809, a specific inhibitor of the alternative pathway C3/C5 convertase (C3bBb). SAR443809 selectively binds to the activated form of factor B (factor Bb) and inhibits alternative pathway activity by blocking the cleavage of C3, leaving the initiation of classical and lectin complement pathways unaffected. Ex vivo experiments with patient-derived paroxysmal nocturnal hemoglobinuria erythrocytes show that, although terminal pathway inhibition via C5 blockade can effectively inhibit hemolysis, proximal complement inhibition with SAR443809 inhibits both hemolysis and C3b deposition, abrogating the propensity for extravascular hemolysis. Finally, intravenous and subcutaneous administration of the antibody in nonhuman primates demonstrated sustained inhibition of complement activity for several weeks after injection. Overall, SAR443809 shows strong potential for treatment of alternative pathway-mediated disorders.
Topics: Animals; Complement Factor B; Erythrocytes; Hemolysis; Complement C3-C5 Convertases; Complement Pathway, Alternative; Immune System Diseases; Humans; Macaca fascicularis; Antibodies; Proteolysis
PubMed: 36897252
DOI: 10.1182/bloodadvances.2022009028 -
Seminars in Immunology Jun 2018
Topics: Animals; Complement Activation; Complement System Proteins; Cytotoxicity, Immunologic; Homeostasis; Humans; Immunity, Innate; Immunotherapy; Kupffer Cells; Neoplasms; Neurogenesis; Neutrophils; Opsonin Proteins; Receptors, Complement
PubMed: 29857931
DOI: 10.1016/j.smim.2018.05.002 -
Malaria Journal Jul 2021There are seven known species of Plasmodium spp. that can infect humans. The human host can mount a complex network of immunological responses to fight infection and one... (Review)
Review
There are seven known species of Plasmodium spp. that can infect humans. The human host can mount a complex network of immunological responses to fight infection and one of these immune functions is phagocytosis. Effective and timely phagocytosis of parasites, accompanied by the activation of a regulated inflammatory response, is beneficial for parasite clearance. Functional studies have identified specific opsonins, particularly antibodies and distinct phagocyte sub-populations that are associated with clinical protection against malaria. In addition, cellular and molecular studies have enhanced the understanding of the immunological pathways and outcomes following phagocytosis of malaria parasites. In this review, an integrated view of the factors that can affect phagocytosis of infected erythrocytes and parasite components, the immunological consequences and their association with clinical protection against Plasmodium spp. infection is provided. Several red blood cell disorders and co-infections, and drugs that can influence phagocytic capability during malaria are also discussed. It is hoped that an enhanced understanding of this immunological process can benefit the design of new therapeutics and vaccines to combat this infectious disease.
Topics: Animals; Anopheles; Erythrocytes; Humans; Malaria, Falciparum; Phagocytosis; Plasmodium falciparum
PubMed: 34271941
DOI: 10.1186/s12936-021-03849-1 -
Nutrients Oct 2015Vitellogenin (Vtg), the major egg yolk precursor protein, is traditionally thought to provide protein- and lipid-rich nutrients for developing embryos and larvae.... (Review)
Review
Vitellogenin (Vtg), the major egg yolk precursor protein, is traditionally thought to provide protein- and lipid-rich nutrients for developing embryos and larvae. However, the roles of Vtg as well as its derived yolk proteins lipovitellin (Lv) and phosvitin (Pv) extend beyond nutritional functions. Accumulating data have demonstrated that Vtg, Lv and Pv participate in host innate immune defense with multifaceted functions. They can all act as multivalent pattern recognition receptors capable of identifying invading microbes. Vtg and Pv can also act as immune effectors capable of killing bacteria and virus. Moreover, Vtg and Lv are shown to possess phagocytosis-promoting activity as opsonins. In addition to these immune-relevant functions, Vtg and Pv are found to have antioxidant activity, which is able to protect the host from oxidant stress. These non-nutritional functions clearly deepen our understanding of the physiological roles of the molecules, and at the same time, provide a sound basis for potential application of the molecules in human health.
Topics: Animals; Antioxidants; Bacteria; Egg Proteins; Fishes; Phosvitin; Receptors, Pattern Recognition; Viruses; Vitellogenins
PubMed: 26506386
DOI: 10.3390/nu7105432 -
Microbiological Research Dec 2023The human complement system is an important part of the innate immune response in the fight against invasive bacteria. Complement responses can be activated... (Review)
Review
The human complement system is an important part of the innate immune response in the fight against invasive bacteria. Complement responses can be activated independently by the classical pathway, the lectin pathway, or the alternative pathway, each resulting in the formation of a C3 convertase that produces the anaphylatoxin C3a and the opsonin C3b by specifically cutting C3. Other important features of complement are the production of the chemotactic C5a peptide and the generation of the membrane attack complex to lyse intruding pathogens. Invasive pathogens like Staphylococcus aureus and several species of the genus Streptococcus have developed a variety of complement evasion strategies to resist complement activity thereby increasing their virulence and potential to cause disease. In this review, we focus on secreted complement evasion factors that assist the bacteria to avoid opsonization and terminal pathway lysis. We also briefly discuss the potential role of complement evasion factors for the development of vaccines and therapeutic interventions.
Topics: Humans; Gram-Positive Cocci; Immunity, Innate; Staphylococcal Infections; Immune System; Immune Evasion
PubMed: 37826985
DOI: 10.1016/j.micres.2023.127512 -
Journal of Innate Immunity 2019The human host has evolved elaborate protection mechanisms to prevent infection from the billions of microorganisms to which it host is exposed and is home. One of these... (Review)
Review
The human host has evolved elaborate protection mechanisms to prevent infection from the billions of microorganisms to which it host is exposed and is home. One of these systems, complement, is an evolutionary ancient arm of innate immunity essential for combatting bacterial infection. Complement permits the efficient labelling of bacteria with opsonins, supports phagocytosis, and facilitates phagocyte recruitment to the site of infection through the production of chemoattractants. However, it is by no means perfect, and certain organisms engage in an evolutionary arms race with the host where complement has become a major target to promote immune evasion. Streptococcus pyogenes is a major human pathogen that causes significant morbidity and mortality globally. S. pyogenes is also a member of an elite group of bacterial pathogens possessing a sophisticated arsenal of virulence determinants capable of interfering with complement. In this review, we focus on these complement evasins, their mechanism of action, and their importance in disease progression. Finally, we highlight new therapeutic options for fighting S. pyogenes, by interfering with one of its main mechanisms of complement evasion.
Topics: Bacterial Proteins; Complement System Proteins; Humans; Immune Evasion; Streptococcal Infections; Streptococcus pyogenes
PubMed: 30269134
DOI: 10.1159/000492944