Complement as part of both the innate and adaptive immune systems plays a central role in our defense against infections. Although its antimicrobial effects have been known for well over 100 years, its significance for boosting our immunity against pathogens has been relatively neglected. It has become apparent only recently that one of the major characteristics of a pathogenic microbe is that it can escape complement attack. All viruses, many bacteria, and certain life forms of fungi and protozoan parasites can hide inside cells, where they are protected from antibodies, complement, and other humoral immune effector mechanisms. Most microbes, however, have extracellular forms, although some of them are not capable of multiplying without the replicative machinery of the host, such as viruses, or the protective intracellular environment.

This Special Issue of FEBS Letters contains 14 articles devoted to the role of complement in microbial infections and is particularly timely because the SARS‐CoV‐2 pandemic has dramatically increased the public interest in microbes and in preventing infections. Below, we will briefly summarize the role of complement in viral and bacterial infections as described in the individual articles belonging to this collection. In addition, the role of complement in the complex infections caused by Aspergillus fungi and Plasmodium falciparum parasites is discussed in their separate articles by Parente et al. [[1]] and Kiyuka et al. [[2]], respectively.

Aspergillus fungi are opportunistic pathogens, yet they can cause multiple types of infections, especially in patients receiving immunosuppressive drugs or suffering from immune deficiency. In immunocompromised individuals, complement, however, is still active but apparently, Aspergillus can escape it and cause an invasive infection. Aspergillus fungi can cause both infectious and allergic lung disease and a tumor‐type aspergilloma. There are different forms of the fungi that interact with the complement system and pentraxins, like C‐reactive protein and PTX‐3. Pentraxins closely co‐operate with the complement system by both activating and regulating it. In a thorough article, Parente et al. [[1]] explain how Aspergillus can cope with these two protein systems.

The causative agents of malaria, and especially its most dangerous species, P. falciparum, are another group of complex organisms with different life forms. Kiyuka et al. [[2]] will give you an update on what is currently known about complement evasion by plasmodia, and how this information could be used for preparing efficient, functional vaccines.

As a medical problem, complement resistance is comparable to antimicrobial resistance (AMR). AMR is a ‘man‐made’ problem that has mostly emerged only during the last 100 years, when antibiotics have been adopted for treating infections in humans and animals. In contrast, the resistance to complement has developed during a very long time in evolution. The emergence of complement‐resistant pathogenic microbes has occurred simultaneously with the development of the complement system in different animals. Complement resistance in microbes has contributed to the creation of the repertoire of pathogenic microbes. AMR poses a threat because we will be losing the most commonly used tools against microbial infections caused by pathogenic and/or opportunistic microbes. The fact that opportunistic microbes, like Acinetobacter, Enterobacter sp., Klebsiella, and Pseudomonas, can cause infections depends usually on a decreased local or generalized immune activity of the host. Then, even if the microbe would be sensitive to complement, it could cause an infection. Real pathogens, however, can survive complement attack in the niches, where they cause infections.

Why is it important to study complement evasion mechanisms of microbes? Complement resistance is an important virulence mechanism of many pathogenic microbes. As with other virulence mechanisms (e.g., adhesion, production of toxins), it is important to know which factors are responsible for the ability of a microbe to avoid complement‐mediated opsonophagocytosis or direct killing. This will be helpful for the development of vaccines, passive antibody therapy, or possible new types of antimicrobials to counteract the resistance mechanism. Learning how microbes or other organisms (like ticks or insects feeding on blood) can inhibit complement could also advise us to develop new therapeutics to suppress overactivity of complement that occurs in many human diseases. Understanding how microbes deal with the complement system helps us also to understand the fundamental mechanisms of the system itself and relative contributions of its individual pathways and components.

From the microbial perspective, complement resistance is important for the ability to survive and multiply in animal hosts. Naturally, many other factors are needed, as well. Microbes need to have the right types of ligands for host receptors and other molecules for attachment and invasion into cells and tissues. Often, they need toxins to provide enough debris for growth and provision of nutrients. In extreme cases, the toxins and infections themselves can be detrimental to the host. The medical impact of microbial infections is enormous and now increasingly appreciated by the current SARS‐CoV‐2 pandemic. While interactions of the SARS‐CoV‐2 with complement are still under study, our current Special Issue of FEBS Letters will provide a panoramic view of what is currently known of interactions between various microbes and the complement system. This will be instructive for studies on other microbes, including the coronaviruses and for any other potential infection threats in the future.

The complement resistance of viruses is discussed thoroughly by Agrawal et al. [[3]]. While pathogenic bacteria are experts in stealing and exploiting host proteins, virulent viruses usually have stolen host genes and modified them for their own purposes. As elegantly indicated in this review, viruses as pathogenic as, for example, the poxviruses mimic complement‐regulating proteins of their hosts. In humans, the regulators usually are composed of major structural units, complement control protein repeats encoded in chromosome 1 in the so‐called regulators of complement activation (RCA) gene cluster. In addition, a mimic for the membrane attack complex inhibitor CD59 can be found in the monkey herpesvirus H. saimiri.

Because of the increasing emergence of problems caused by viruses, it is obvious that we need to learn more about their complement escape mechanisms. Dengue viruses belong to a larger group of flaviviruses that cause different types of infections (West Nile virus, yellow fever virus, and Zika virus). As explained by Carr et al. [[4]], complement can have multiple roles in the mosquito‐borne dengue virus infections. In some situations, antibody‐mediated immunity and complement can be protective, but on some other occasions, they can severely promote the inflammatory response and lead to a severe complication, the capillary leak syndrome. The fact that viruses have developed multiple functional interactions with complement factors provides a solid and unbiased proof for the importance of complement as an immune defense mechanism.

This issue showcases eight reviews on the interactions of complement with various bacteria. Staphylococci are masters of immune evasion, as illustrated in the article by de Vor et al. [[5]]. They can block complement at many steps, galvanize neutrophils, and form biofilms for their protection (e.g., in wound infections and on implants). In this review, the reader can have a look at the largest repertoire of complement‐inhibiting factors known for any bacterium and mechanisms of biofilm generation. Interestingly, the latter show differences between S. epidermidis and S. aureus, common causes of infections both on surfaces and deep inside tissues.

Streptococcus pneumoniae (pneumococcus) causes bacterial upper respiratory tract infections, pneumonia, sinusitis, and otitis. It can also cause meningitis and septic infections. Pneumococci and other streptococci are discussed by Syed et al. [[6]]. Like other pathogens, group A streptococci (S. pyogenes) and pneumococci exploit soluble complement inhibitors, particularly factor H for complement escape. For this, they use specific surface proteins, most commonly the M protein or the PspC family proteins. Other important virulence factors are cytolysins, streptolysin and pneumolysin, that generate pores on cells somewhat similarly as the complement membrane attack complex (MAC). The respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis, as elegantly presented by Riesbeck [[7]], also exploit the soluble complement inhibitors, C4bp and factor H, for their protection. In addition, both have been found to bind vitronectin, which may help in preventing bactericidal complement lysis of these Gram‐negative bacteria. The bacteria use multiple types of surface molecules for complement escape and for adhesion to host cells.

The Gram‐negative bacteria Salmonella and Yersinia can cause both enteric and systemic infections. Krukonis and Thomson [[8]] describe strategies underlying their ability to cause systemic infections and invade deep into tissues. These properties are to a large extent based on their ability to hijack complement inhibitors, interfere with MAC formation, and proteolytically destroy complement proteins. As explained, different components of the bacteria contribute to these functions.

Bacterial sepsis is an emergency in the medical care. It can be caused by many bacteria, notably by staphylococci, pneumococci, meningococci, or Gram‐negative enteric bacteria. This is a situation where complement activation and other inflammatory mechanisms have turned into our enemies. Efforts have been made to search for means to inhibit this overwhelming inflammatory condition. Mollnes and Huber‐Lang [[9]] provide us an update on ongoing attempts to use state‐of‐the‐art complement inhibitors and Toll‐like receptor blockers to save patients.

Spirochetes constitute a peculiar group of bacteria with distinct characteristics. Barbosa et al. [[10]] present us Leptospira sp., a large group that includes both pathogens and nonpathogens. This has made it possible to perform a meaningful comparison of their ability to resist killing by complement, for example, in human serum. Not surprisingly, yet importantly, these studies have shown that the complement‐resistant Leptospira sp. are also the pathogenic ones. They can bind complement inhibitors from the host and exploit their own and host proteases for their benefit. Leptospires are important zoonotic disease pathogens in the tropics, especially under low hygienic conditions. In contrast, in the Northern Hemisphere, both in Europe and in North America, spirochetes of the Borrelia genus cause borreliosis, also called Lyme disease. Dulipati et al. [[11]] provide an account of their mechanisms of complement evasion, describing particularly the various spirochetal proteins that mediate factor H binding or use other means of complement escape. Borrelia spirochetes are spread by ticks and can cause insidious infections with different clinical manifestations. No vaccines exist against borreliosis, but this disease is one where complement regulator‐binding proteins could be considered as candidates. This thinking is based on the potential dual benefit of their use: Indeed, antibodies generated against the factor H‐binding proteins would target the immune response against the bacteria and also neutralize an important virulence mechanism on borrelia surface, thereby sensitizing the bacteria to complement killing.

The relevance of the complement for the rational design of vaccines is also covered by two reviews in this Special Issue, and here, we discuss how the lessons learned from these studies may apply to SARS‐CoV‐2 management. In 2008, we wrote an article about considering microbial inhibitors as vaccines [[12]]. To our great satisfaction, this has now become reality, because two novel vaccines against group B meningococcus based on complement factor H‐binding proteins are available on the market [[13]]. The novel concept was to realize that, for an efficient vaccine‐induced immune response, it is important to understand the key virulence mechanisms of the disease‐causing pathogen. In the case of group B meningococcus, this meant that the ability of the bacterium to escape complement would be neutralized by the vaccine‐induced immune response. This may occur during normal development of immunity that follows an infection. As described by Lewis and Ram [[14]], both Neisseria meningitidis and N. gonorrhoeae are specific human pathogens. This specificity is principally due to the fact that these two bacteria bind human inhibitors of complement factor H‐ and C4b‐binding protein (C4bp), respectively. This strongly advocates the importance of complement evasion as a key factor determining the pathogenicity of the microbes. Since the mortality for meningococcal infections, meningitis and sepsis, is very high, we cannot rely on naturally developing immunity but need to intervene efficiently and as fast as possible by antibiotics in acute infections. In areas with higher risk of infections, vaccines provide a safer means of prevention.

Similar key questions concern now also SARS‐CoV‐2: Is the risk of having an infection and its potential serious consequences high enough to warrant wide‐scale vaccination? Without major doubt, the answer to this question is yes. Experience has shown that the key means for future protection against the coronavirus infection will be vaccination and vaccines are intensively under development. But do they consider sufficiently the virulence mechanisms of the virus? And do we know enough of the virulence mechanisms, particularly about the immune escape mechanisms? What is it that makes the virus so pathogenic? How does it escape complement‐mediated neutralization or opsonophagocytosis? Could antibodies, naturally developing or vaccine‐induced, even enhance infectivity of the virus? We are not even fully sure yet whether protective immunity develops, and particularly, for how long does it last.

Another important point that we raised about vaccination was that if proteins included in vaccines strongly bind host proteins, then they may lose part of their ability to raise a proper immune response [[12]]. Many pathogens escape complement attack by binding the soluble complement inhibitor factor H, a strategy that also the human body uses to distinguish self from nonself [[15]]. Thus, it is natural to have microbial factor H‐binding proteins (FHBP) in vaccines, as is the case in group B meningococcal vaccines [[13]]. If vaccines contain proteins that bind too strongly to host factor H, they may be scavenged away from reaching antigen‐capturing dendritic cells. Also, since factor H is an inhibitor of complement, factor H binding to the vaccine component could limit the efficacy of the vaccine by preventing the natural adjuvant effect that complement has. Activation products of especially the complement component C3 (C3b, iC3b, C3dg, and C3d) remain covalently bound to target antigens that activate complement. They are important for the uptake of the antigens by antigen‐presenting cells (dendritic cells, macrophages, and B cells) via the complement receptors CR1 (CD35), CR2 (CD21), and CR3 (CD11b,18). Complement receptors and their utilization by microbes are discussed in this issue by Lukácsi et al. [[16]]. While these receptors serve an important function in the phagocytosis of microbes, they can also be misused for microbial entry into host cells.

If vaccine antigens form complexes with host proteins, autoimmunity could arise in the worst case. For this to happen, the FHBP‐factor H complexes should be taken up by factor H‐reactive B cells. With the help provided by the microbial protein reactive CD4⁺ helper T cells, these B cells could become activated and start generating autoantibodies against factor H. It is known that autoantibodies against factor H occur in and cause one type of atypical hemolytic uremic syndrome (aHUS) [[17]]. The origin of these antibodies is not known, but could involve a preceding microbial infection. A means to avoid loss of efficiency of vaccination as well as the risk for autoimmunization could be to modify the vaccine antigens so that they maintain immunogenicity but do not bind so effectively to host proteins [[12]]. Animal experiments have, indeed, shown that stronger immune responses can be achieved by vaccine FHBP antigens that have been modified to disable factor H binding [[18]].

As with other pathogens, it is apparent that the SARS‐CoV‐2 virus needs to escape complement attack. However, so far the mechanisms are not yet known. Since the complement system is one of the major effector mechanisms of immune responses, it would be important to delineate how future vaccines could induce an appropriate and sufficiently strong response to neutralize the SARS‐CoV‐2 virus. In essence, such a response should be able to block the key virulence factors and mechanisms of the virus. Prevention of virus binding to its receptors by vaccine‐induced antibodies is important but not sufficient. In fact, the antibodies raised by the vaccine should also activate the complement system in order to promote opsonophagocytosis and direct neutralization of the virus. Complement activation is also important for triggering a cell‐mediated immune response, because C3 activation products covalently linked to viral antigens mediate pathogen uptake and delivery for presentation to T cells in the secondary immune tissues. While an efficient protective immune response is needed, the other key aspect is the safety of the vaccine. With a focused and carefully targeted, functional vaccine approach, the potential side effects become less likely.

To conclude, we hope that individual articles in this Special Issue will provide a view to the most relevant interactions between complement and various microbes. The general feeling and understanding in the field, as reflected by the articles, is that this area of research is important for the development of vaccines and potential other therapeutic means to combat serious infections. Understanding the fundamentals of microbial virulence in general, and of complement resistance specifically, will be instructive for designing preventive tools and vaccines to new emerging pathogens.

作为先天性和适应性免疫系统的一部分，补体在我们抵抗感染的防御中起着核心作用。尽管其抗微生物作用已经有100多年的历史了，但它在增强我们对病原体免疫力方面的重要性却相对被忽略了。直到最近才变得明显，致病微生物的主要特征之一是它可以逃脱补体攻击。所有病毒，许多细菌以及某些生命形式的真菌和原生动物寄生虫都可以藏在细胞内部，这些细胞可以免受抗体，补体和其他体液免疫效应器机制的保护。然而，大多数微生物具有细胞外形式，尽管其中一些微生物在没有宿主的复制机制（例如病毒）或保护性细胞内环境的情况下无法繁殖。

FEBS信件的这期特刊包含14篇文章，专门讨论补体在微生物感染中的作用，由于SARS-CoV-2大流行极大地提高了公众对微生物和预防感染的兴趣，因此特别及时。下面，我们将简要总结补体在病毒和细菌感染中的作用，如该收藏集中的各个文章所述。此外，Parente等人在其单独的文章中讨论了补体在曲霉菌真菌和恶性疟原虫寄生虫引起的复杂感染中的作用。[ [1] ]和Kiyuka等。[ [2] ]。

曲霉菌是机会病原体，但它们可引起多种类型的感染，尤其是在接受免疫抑制药物或患有免疫缺陷的患者中。在免疫功能低下的个体中，补体仍然有效，但显然，曲霉菌可以逃脱它并引起侵袭性感染。曲霉菌真菌可引起传染性和过敏性肺部疾病以及肿瘤型曲霉菌。与补体系统和五聚毒素相互作用的真菌有多种形式，例如C反应蛋白和PTX-3。Pentraxins通过激活和调节补体系统密切配合。在一篇详尽的文章中，Parente等人。[ [1] ]解释如何曲霉可以应付这两种蛋白质系统。

疟疾的病原体，尤其是其最危险的物种恶性疟原虫，是另一类具有不同生命形式的复杂生物。Kiyuka等。[ [2] ]将为您提供有关疟原虫逃避补体的最新知识，以及如何将这些信息用于制备有效的功能性疫苗的最新信息。

作为医学问题，补体耐药性可与抗菌药耐药性（AMR）相媲美。AMR是一个“人为”问题，仅在最近100年来才出现，当时已采用抗生素治疗人类和动物的感染。相反，对补体的抗性在很长的进化过程中发展起来。耐补体病原性微生物的出现与不同动物中补体系统的发展同时发生。微生物中的补体抗性促成了病原性微生物库的建立。AMR构成威胁，因为我们将失去最常用的工具来抵抗由病原性和/或机会性微生物引起的微生物感染。不动杆菌之类的机会微生物，肠杆菌属，克雷伯菌和假单胞菌可引起感染的原因通常取决于宿主局部或全身免疫活性的降低。然后，即使微生物对补体敏感，也可能引起感染。但是，真正的病原体可以在生态位的补体攻击中幸存下来，从而引起感染。

为什么研究微生物的补体逃逸机制为什么很重要？补体抗性是许多病原微生物的重要毒力机制。与其他毒力机制（例如黏附，毒素产生）一样，重要的是要知道哪些因素导致微生物避免补体介导的调理吞噬作用或直接杀死微生物的能力。这将有助于疫苗的开发，被动抗体疗法或可能的新型抗菌素，以抵消耐药性机制。了解微生物或其他生物（如tick或昆虫以血液为食）如何抑制补体也可能建议我们开发新的疗法来抑制许多人类疾病中发生的补体过度活跃。

从微生物的角度来看，补体抗性对于在动物宿主中生存和繁殖的能力很重要。自然，也需要许多其他因素。微生物需要具有正确的宿主受体配体类型和其他分子来附着和侵入细胞和组织。通常，他们需要毒素才能提供足够的碎片来生长和提供营养。在极端情况下，毒素和感染本身可能对宿主有害。微生物感染的医学影响是巨大的，现在，由当前的SARS-CoV-2大流行日益引起人们的重视。尽管SARS‐CoV‐2与补体的相互作用仍在研究中，但我们当前的FEBS特刊特刊将提供目前已知的各种微生物与补体系统之间相互作用的全景图。这对于研究其他微生物，包括冠状病毒以及将来的任何其他潜在感染威胁，将具有指导意义。

Agrawal等人充分讨论了病毒的补体抗性。[ [3] ]。病原菌是窃取和利用宿主蛋白的专家，而强毒病毒通常会窃取宿主基因，并出于自身目的对其进行修饰。正如本评论所明确指出的，致病性病毒（例如痘病毒）模仿其宿主的补体调节蛋白。在人类中，调节子通常由主要结构单元组成，即所谓的补体激活调节子（RCA）基因簇中第1号染色体编码的补体控制蛋白重复序列​​。另外，在猴疱疹病毒赛米氏杆菌中发现了膜攻击复合物抑制剂CD59的模拟物。

由于病毒引起的问题越来越多地出现，因此显然我们需要更多地了解其补码逃逸机制。登革热病毒属于一大类黄病毒，它们引起不同类型的感染（西尼罗河病毒，黄热病病毒和寨卡病毒）。如Carr等人所述。[ [4]]，补体在蚊媒登革热病毒感染中可能具有多种作用。在某些情况下，抗体介导的免疫和补体可以起到保护作用，但在其他情况下，它们可以严重促进炎症反应并导致严重并发症，即毛细血管渗漏综合征。病毒已经与补体因子发生了多种功能相互作用，这一事实为补体作为免疫防御机制的重要性提供了坚实而公正的证据。

本期展示了八篇有关补体与各种细菌相互作用的评论。如de Vor等人的文章所述，葡萄球菌是免疫逃逸的大师。[ [5] ]。它们可以在许多步骤中阻断补体，刺激中性粒细胞，并形成生物膜对其提供保护（例如，在伤口感染和植入物中）。在这篇评论中，读者可以了解任何细菌和生物膜生成机制已知的最大的补体抑制因子库。有趣的是，后者显示出表皮葡萄球菌和金黄色葡萄球菌之间的差异，这是表面和内部深部组织感染的常见原因。

肺炎链球菌（肺炎球菌）引起细菌上呼吸道感染，肺炎，鼻窦炎和中耳炎。它还可能导致脑膜炎和败血性感染。肺炎球菌和其他链球菌由Syed等人讨论。[ [6] ]。像其他病原体一样，A组链球菌（化脓性链球菌）和肺炎球菌也利用可溶性补体抑制剂，尤其是H因子来逃避补体。为此，他们使用特定的表面蛋白，最常见的是M蛋白或PspC家族蛋白。其他重要的毒力因子是溶细胞素，链球菌溶血素和肺炎球菌溶血素，它们在细胞上产生的孔与补膜攻击复合物（MAC）相似。呼吸道病原体流感嗜血杆菌如Riesbeck [ 7]优雅地提出的，卡他莫拉氏菌和卡他莫拉氏菌也利用可溶性补体抑制剂C4bp和H因子来提供保护。此外，已发现两者都结合玻连蛋白，这可能有助于防止这些革兰氏阴性细菌的杀菌补体裂解。细菌使用多种类型的表面分子进行补体逃逸和粘附至宿主细胞。

革兰氏阴性细菌沙门氏菌和耶尔森氏菌可引起肠道和全身感染。Krukonis和Thomson [ [8] ]描述了引起系统性感染并深入组织的能力的策略。这些特性很大程度上取决于它们劫持补体抑制剂，干扰MAC形成以及蛋白水解破坏补体蛋白的能力。如所解释的，细菌的不同成分有助于这些功能。

细菌性败血症是医疗中的紧急情况。它可能是由许多细菌引起的，尤其是葡萄球菌，肺炎球菌，脑膜炎球菌或革兰氏阴性肠细菌。在这种情况下，补体激活和其他炎症机制已成为我们的敌人。已努力寻找抑制这种压倒性炎症的方法。Mollnes和Huber-Lang [ [9] ]为我们提供了有关使用最先进的补体抑制剂和Toll样受体阻滞剂挽救患者的最新尝试。

螺旋体构成具有独特特征的特殊细菌群。Barbosa等。[ [10] ]向我们介绍了钩端螺旋体，这是一个既包括病原体又包括非病原体的大群体。这使得可以对它们在例如人血清中的抗补体杀伤能力进行有意义的比较。毫不奇怪，但重要的是，这些研究表明补体耐药性钩端螺旋体sp。也是致病的。它们可以结合宿主的补体抑制剂，并利用其自身和宿主蛋白酶来获得益处。钩端螺旋体是热带地区重要的人畜共患病病原体，尤其是在低卫生条件下。相反，在北半球，无论在欧洲还是在北美，螺旋体属的螺旋体都会引起疏螺旋体病，也称为莱姆病。Dulipati等。[ [11] ]提供了其补体逃逸机制的说明，特别描述了介导H因子结合或使用其他补体逃逸手段的各种螺旋蛋白。博雷利亚螺旋体通过tick传播，并可能引起具有不同临床表现的隐性感染。目前尚无针对鲍氏菌病的疫苗，但这种疾病是补体调节剂结合蛋白可以考虑的候选疾病。这种想法基于使用它们的潜在双重好处：确实，针对H结合蛋白产生的抗体将靶向针对细菌的免疫反应，并中和了疏螺旋体表面的重要毒力机制，从而使细菌对杀伤行为具有补充作用。

本期特刊中的两次评论也涵盖了补品与疫苗合理设计的相关性，在这里，我们讨论了从这些研究中学到的经验教训如何适用于SARS-CoV-2的管理。在2008年，我们写了一篇有关考虑将微生物抑制剂作为疫苗的文章[ [12] ]。令我们非常满意的是，这已经成为现实，因为市场上有两种基于补体因子H结合蛋白的针对B组脑膜炎球菌的新型疫苗[13]。]。这个新概念是要认识到，对于有效的疫苗诱导的免疫反应，重要的是要了解引起疾病的病原体的关键毒力机制。对于B组脑膜炎球菌，这意味着该细菌逃脱补体的能力将被疫苗诱导的免疫反应所中和。这可能在感染后免疫正常发育过程中发生。如Lewis和Ram [ 14 ]所述，脑膜炎奈瑟氏球菌和淋病奈瑟氏球菌都是特定的人类病原体。这种特异性主要是由于这两种细菌分别结合人类补体因子H和C4b结合蛋白（C4bp）抑制剂。这强烈主张逃避补体作为确定微生物致病性的关键因素的重要性。由于脑膜炎球菌感染，脑膜炎和败血症的死亡率很高，我们不能依靠自然发展的免疫力，而需要在急性感染中通过抗生素进行尽可能快速有效的干预。在感染风险较高的地区，疫苗提供了更安全的预防手段。

现在，SARS-CoV-2也涉及到类似的关键问题：感染的风险及其潜在的严重后果是否足够高，可以进行大规模疫苗接种？毫无疑问，这个问题的答案是肯定的。经验表明，未来预防冠状病毒感染的关键手段将是接种疫苗，并且正在大力开发疫苗。但是他们是否充分考虑了病毒的毒力机制？我们是否对毒力机制了解得足够多，尤其是关于免疫逃逸机制？是什么使病毒如此致病？它如何逃避补体介导的中和或调理吞噬作用？自然发展或疫苗诱导的抗体能否增强病毒的感染性？我们甚至还不确定是否会产生保护性免疫力，

关于疫苗接种，我们提出的另一个重要观点是，如果疫苗中包含的蛋白质与宿主蛋白质牢固结合，那么它们可能会丧失部分能力，无法引发适当的免疫反应[ [12] ]。许多病原体通过结合可溶性补体抑制剂因子H逃脱补体攻击，人体也使用这种策略将自身与非自身区分开[15 ]。因此，疫苗中含有微生物因子H结合蛋白（FHBP）是很自然的，就像B组脑膜炎球菌疫苗一样[ [13]]。如果疫苗含有与宿主因子H结合太强的蛋白质，则它们可能会清除而无法到达捕获抗原的树突状细胞。而且，由于因子H是补体的抑制剂，因子H与疫苗成分的结合可通过阻止补体具有的天然佐剂作用而限制疫苗的功效。特别是补体成分C3的激活产物（C3b，iC3b，C3dg和C3d）保持与激活补体的靶抗原共价结合。它们对于抗原呈递细胞（树突状细胞，巨噬细胞和B细胞）通过补体受体CR1（CD35），CR2（CD21）和CR3（CD11b，18）吸收抗原非常重要。Lukácsi等人在本期中讨论了补体受体及其被微生物利用的问题。[ [16]]。尽管这些受体在微生物的吞噬作用中起着重要的作用，但它们也可能被误用于微生物进入宿主细胞。

如果疫苗抗原与宿主蛋白形成复合物，则在最坏的情况下可能会产生自身免疫。为此，FHBP H因子复合物应被H因子反应性B细胞吸收。在微生物蛋白反应性CD4 ⁺辅助性T细胞的帮助下，这些B细胞可能被激活并开始产生针对H因子的自身抗体。已知针对H因子的自身抗体发生并引起一种非典型溶血性尿毒症综合征（aHUS） ）[ [17]]。这些抗体的来源尚不清楚，但可能涉及先前的微生物感染。避免降低疫苗接种效率以及自身免疫风险的一种方法可能是修饰疫苗抗原，以使其保持免疫原性，但不能与宿主蛋白有效结合[12 ]。实际上，动物实验表明，已被修饰以禁用H因子结合的疫苗FHBP抗原可以实现更强的免疫反应[ [18] ]。

与其他病原体一样，SARS-CoV-2病毒显然需要逃脱补体攻击。但是，到目前为止，该机制尚不清楚。由于补体系统是免疫反应的主要效应器机制之一，因此重要的是要描述未来的疫苗如何诱导适当和足够强的反应来中和SARS-CoV-2病毒。从本质上讲，这种反应应该能够阻止病毒的关键毒力因子和机制。通过疫苗诱导的抗体防止病毒与其受体结合很重要，但还不够。实际上，疫苗产生的抗体也应激活补体系统，以促进调理吞噬作用和病毒的直接中和作用。补体激活对于触发细胞介导的免疫反应也很重要，因为与病毒抗原共价连接的C3激活产物介导病原体的吸收和传递，从而呈递给次级免疫组织中的T细胞。虽然需要有效的保护性免疫应答，但另一个关键方面是疫苗的安全性。通过有针对性和精心针对性的功能疫苗方法，潜在的副作用变得更少了。

总而言之，我们希望本期特刊中的各个文章能够为补体与各种微生物之间最相关的相互作用提供一个视角。文章所反映的，该领域的一般感觉和理解是，这一研究领域对于开发疫苗和对抗严重感染的潜在其他治疗手段非常重要。总体上了解微生物毒力的基础知识，尤其是对补体耐药性的基础知识，对于设计针对新兴病原体的预防工具和疫苗具有指导意义。