Febs Letters

doi: 10.1002/1873-3468.13414pmid: N/A

Meri, Seppo; Jarva, Hanna

doi: 10.1002/1873-3468.13892pmid: 32830321

Parente, Raffaella; Doni, Andrea; Bottazzi, Barbara; Garlanda, Cecilia; Inforzato, Antonio

doi: 10.1002/1873-3468.13744pmid: 31994174

Aspergillosis is a life‐threatening infection mostly affecting immunocompromised individuals and primarily caused by the saprophytic fungus Aspergillus fumigatus. At the host–pathogen interface, both cellular and humoral components of the innate immune system are increasingly acknowledged as essential players in the recognition and disposal of this opportunistic mold. Fundamental hereof is the contribution of the complement system, which deploys all three activation pathways in the battle against A. fumigatus, and functionally cooperates with other soluble pattern recognition molecules, including pentraxins. In particular, preclinical and clinical observations point to the long pentraxin PTX3 as a nonredundant and complement‐dependent effector with protective functions against A. fumigatus. Based on past and current literature, here we discuss how the complement participates in the immune response to this fungal pathogen, and illustrate its crosstalk with the pentraxins, with a focus on PTX3. Emphasis is placed on the molecular mechanisms underlying such processes, the genetic evidence from human epidemiology, and the translational potential of the currently available knowledge.

Kiyuka, Patience Kerubo; Meri, Seppo; Khattab, Ayman

doi: 10.1002/1873-3468.13772pmid: 32181490

The malaria parasite has for long been thought to escape host complement attack as a survival strategy. However, it was only recently that complement evasion mechanisms of the parasite were described. Simultaneously, the role of complement in antibody‐mediated naturally acquired and vaccine‐induced protection against malaria has also been reported. Such findings should be considered in future vaccine design, given the current need to develop more efficacious vaccines against malaria. Parasite antigens derived from molecules mediating functions crucial for parasite survival, such as complement evasion, or parasite antigens against which antibody responses lead to an efficient complement attack could present new candidates for vaccines. In this review, we discuss recent findings on complement evasion by the malaria parasites and the emerging role of complement in antibody‐mediated protection against malaria. We emphasize that immune responses to vaccines based on complement inhibitors should not only induce complement‐activating antibodies but also neutralize the escape mechanisms of the parasite.

Agrawal, Palak; Sharma, Samriddhi; Pal, Pradipta; Ojha, Hina; Mullick, Jayati; Sahu, Arvind

doi: 10.1002/1873-3468.13856pmid: 32506518

Viruses are obligate parasites of cellular hosts and therefore are constantly confronted with the host immune system. Evasion of innate immunity mechanisms by viruses is paramount for the establishment of their infection. The complement system can directly neutralize viruses and also augments adaptive immune responses against them. This system, therefore, is central to host innate immune surveillance, and viruses have evolved a multitude of ways to escape its assault. A major strategy employed by viruses is the molecular mimicry of human complement regulators, namely regulators of complement activation (RCA) proteins and CD59. Herein, we outline up‐to‐date information on the structure, function and role of viral homologs of the human complement regulators in viral pathogenesis.

Carr, Jillian M.; Cabezas‐Falcon, Sheila; Dubowsky, Joshua G.; Hulme‐Jones, Jarrod; Gordon, David L.

doi: 10.1002/1873-3468.13730pmid: 31943152

Dengue disease is an inflammatory‐driven pathology, and complement overactivation is linked to disease severity and vascular leakage. Additionally, dysregulation of complement alternative pathway (AP) components has been described, such as upregulation of complement factor D and downregulation of complement factor H (FH), which activate and inhibit the AP, respectively. Thus, the pathology of severe dengue could in part result from AP dysfunction, even though complement and AP activation usually provide protection against viral infections. In dengue virus‐infected macrophages and endothelial cells (ECs), the site of replication and target for vascular pathology, respectively, the AP is activated. The AP activation, reduced FH and vascular leakage seen in dengue disease in part parallels other complement AP pathologies associated with FH deficiency, such as atypical haemolytic uraemic syndrome (aHUS). aHUS can be therapeutically targeted with inhibitors of complement terminal activity, raising the idea that strategies such as inhibition of complement or delivery of FH or other complement regulatory components to EC may be beneficial to combat the vascular leakage seen in severe dengue.

Vor, Lisanne; Rooijakkers, Suzan H. M.; Strijp, Jos A. G.

doi: 10.1002/1873-3468.13767pmid: 32144756

Staphylococcus aureus and Staphylococcus epidermidis can cause many types of infections, ranging from skin infections to implant‐associated infections. The primary innate immune response against bacterial infections involves complement activation, recruitment of phagocytes (most importantly neutrophils), and subsequent killing of the pathogen. However, staphylococci are not innocent bystanders; they actively obstruct this immune attack. To do that, S. aureus secretes several immune‐evasion proteins to resist attack by the innate immune system. Furthermore, S. aureus and S. epidermidis are known for their ability to form biofilms on implanted medical devices and host tissues, which provides another important immune‐evasion mechanism. Understanding these different strategies to resist immune attack will help to develop novel therapies against staphylococcal infections.

Syed, Shahan; Viazmina, Larisa; Mager, Riccardo; Meri, Seppo; Haapasalo, Karita

doi: 10.1002/1873-3468.13872pmid: 32594520

Streptococci are a broad group of Gram‐positive bacteria. This genus includes various human pathogens causing significant morbidity and mortality. Two of the most important human pathogens are Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A streptococcus or GAS). Streptococcal pathogens have evolved to express virulence factors that enable them to evade complement‐mediated attack. These include factor H‐binding M (S. pyogenes) and pneumococcal surface protein C (PspC) (S. pneumoniae) proteins. In addition, S. pyogenes and S. pneumoniae express cytolysins (streptolysin and pneumolysin), which are able to destroy host cells. Sometimes, the interplay between streptococci, the complement, and antistreptococcal immunity may lead to an excessive inflammatory response or autoimmune disease. Understanding the fundamental role of the complement system in microbial clearance and the bacterial escape mechanisms is of paramount importance for understanding microbial virulence, in general, and, the conversion of commensals to pathogens, more specifically. Such insights may help to identify novel antibiotic and vaccine targets in bacterial pathogens to counter their growing resistance to commonly used antibiotics.

Riesbeck, Kristian

doi: 10.1002/1873-3468.13758pmid: 32053211

All infective bacterial species need to conquer the innate immune system in order to colonize and survive in their hosts. The human respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis are no exceptions and have developed sophisticated mechanisms to evade complement‐mediated killing. Both bacterial species carry lipooligosaccharides preventing complement attacks and attract and utilize host complement regulators C4b binding protein and factor H to inhibit the classical and alternative pathways of complement activation, respectively. In addition, the regulator of the terminal pathway of complement activation, vitronectin, is hijacked by both bacteria. An array of different outer membrane proteins (OMP) in H. influenzae and M. catarrhalis simultaneously binds complement regulators, but also plasminogen. Several of the bacterial complement‐binding proteins are important adhesins and contain highly conserved regions for interactions with the host. Thus, some of the OMP are viable targets for new therapeutics, including vaccines aimed at preventing respiratory tract diseases such as otitis media in children and exacerbations in patients suffering from chronic obstructive pulmonary disease.

Krukonis, Eric S.; Thomson, Joshua J.

doi: 10.1002/1873-3468.13771pmid: 32170725

Pathogens that colonize deep tissues and spread systemically encounter the innate host resistance mechanism of complement‐mediated lysis and complement opsonization leading to engulfment and degradation by phagocytic cells. Yersinia and Salmonella species have developed numerous strategies to block the antimicrobial effects of complement. These include recruitment of complement regulatory proteins factor H, C4BP, and vitronectin (Vn) as well as interference in late maturation events such as assembly of C9 into the membrane attack complex that leads to bacterial lysis. This review will discuss the contributions of various surface structures (proteins, lipopolysaccharide, and capsules) to evasion of complement‐mediated immune clearance of the systemic pathogens Yersiniae and Salmonellae. Bacterial proteins required for recruitment of complement regulatory proteins will be described, including the details of their interaction with host regulatory proteins, where known. The potential role of the surface proteases Pla (Yersinia pestis) and PgtE (Salmonella species) on the activity of complement regulatory proteins will also be addressed. Finally, the implications of complement inactivation on host cell interactions and host cell targeting for type 3 secretion will be discussed.