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Inflammatory responses to infection: The Dutch contribution
Abstract
This paper is dedicated to Professor Joep Lange, a Dutch pioneer in AIDS research and a great protagonist of access to effective antiretroviral therapy for all. On July 17 this year, Joep died in the plane crash in Ukraine on his way to the AIDS conference in Australia. a b s t r a c t At any given moment, our body is under attack by a large variety of pathogens, which aim to enter and use our body to propagate and disseminate. The extensive cellular and molecular complexity of our immune system enables us to efficiently eliminate invading pathogens or at least develop a condition in which propagation of the microorganism is reduced to a minimum. Yet, the evolutionary pressure on pathogens to circumvent our immune defense mechanisms is immense, which continuously leads to the development of novel pathogenic strains that challenge the health of mankind. Understanding this battle between pathogen and the immune system has been a fruitful area of immunological research over the last century and will continue to do so for many years.
In this review, which has been written on the occasion of the 50th anniversary of the Dutch Society for Immunology, we provide an overview of the major contributions that Dutch immunologists and infection biologists have made in the last decades on the inflammatory response to viral, bacterial, fungal or parasitic infections. We focus on those studies that have addressed both the host and the pathogen, as these are most interesting from an immunological point of view. Although it is not possible to completely cover this comprehensive research field, this review does provide an interesting overview of Dutch research on inflammatory responses to infection.
Originally, the immune system of multicellular organisms evolved for the defence against microorganisms. During their evolution, vertebrates and especially mammals developed a very sophisticated immune system consisting of an innate and an adaptive arm. Despite this sophistication, pathogenic microorganisms may win the battle, in the worst case leading to death of the mammalian host.
The insight of scientists in the pathophysiology of infection and in host defence emerged slowly over the past centuries. Although the Dutch inventor of the microscope, Antoni van Leeuwenhoek, had discovered microbes around 1675, and the visionary scholar Girolamo Frascoro had postulated seminaria (small seeds or "germs") as causes of communicable diseases already in 1546, the microbial discoveries of Pasteur and Koch were needed to establish the microbial pathogenesis of infectious diseases. Dutch scientists, especially those of the "Delft school" (Beijerinck, Kluyver, Van Niel), delivered important contributions in the early days of microbiology, i.e. during the end of the 19th century and the first decades of the 20th century [1] . In fact, it was Martinus Beijerinck who introduced the term "virus" in 1898, for the filterable agent infecting tobacco plants, which he called 'contagium vivum fluidum' and which is now is known as tobacco mosaic virus [2] .
Relevant discoveries in especially parasitology were made by scientists (Swellengrebel, Schüffner) in The Netherlands East Indies (Indonesia) in the first half of the twentieth century [3] . However, significant research dealing with the host immune response to infection, following the work of Ehrlich, Metchnikoff and von Behring, was not performed in The Netherlands. Vaccine development and antiserum production, "applied immunology", had started in 1919 in The Netherlands, coming to full bloom after 1953 under the leadership of Hans Cohen.
In this paper, which was written on the occasion of the 50th anniversary of the Dutch Society for Immunology, we describe the major research activities and accomplishments of research dealing with the immunology of infectious diseases in The Netherlands, during that era. Although separating this area of immunological research from other areas is artificial, we had to be rather strict in our selection, i.e., to be included in this overview, research had to Deletion of antigen-reactive T cells in HIV-1 infection is driven by aspecific T cell activation [8] 1995 HIV-1 specific CD8 T cells do not protect against the progression of HIV-infection to AIDS [7] 1996 Initial viral rebounds during HIV-1 suppression caused by treatment-induced CD4 T cell increase [12] 1996 CD4 T cell loss in HIV-1 infection is not due to proliferation-induced exhaustion [4] 1998 Extracellular granzymes A and B present in plasma and increases upon HIV-1 and EBV infection [126] 2000
Identification of DC-SIGN and molecular mechanism how HIV-1 transmission by DCs occurs [13,127] 2000 HIV-1 variants using coreceptor CXCR4 accelerate CD4 T cell loss by infecting naïve T cells [6] 2000
T-cell proliferation and deletion in HIV-1 is a consequence of generalized T cell activation [9] 2007 Langerhans cells are protected from HIV-1 infection by the C-type lectin receptor langerin [14] 2009
Sugar-specific signaling through DC-SIGN shapes immunity to viruses and bacteria [15] 2010 HIV-1 variants with long variable loops in envelope escape antibody neutralization [10] 2010 Cross-reactive neutralizing antibodies do not protect against disease progression in HIV-1 [11] Influenza 1999 Polyclonal memory T cell populations to influenza provide protection against a range of viral variants [16] Identification of immunogenic peptides from HPV16 E6 and E7 that can be used for vaccination [37] 1996 Evidence for natural immunity against HPV16 epitopes in patients with HPV16+ cervical lesions [38] 1999 Only cervical precursor lesions with a persistent HPV infection show progression to cancer [39] 2009 Vaccination with long peptides from HPV16 can induce remission of HPV-induced lesions [40] Other 1977 Cellular immune response to vaccinia virus in humans is associated with HLA [41] 1978 Measles virus can enter and be activated inside resting lymphocytes [42] 1988 Sensitivity to lymphomas by murine leukemia virus is determined by MHCII-regulated immunity [128] 1989 Successful immunotherapy with CD8 T cells directed against an epitope in an adenoviral protein [129] 2010 SARS in aged macaques shows exacerbated innate response; type I IFN as potential intervention [43] 2010-13 IFN␥-production upon LCMV infection dramatically alters hematopoiesis in bone marrow [48-50] 2012 Double-stranded RNA upon cellular infection with picornavirus is recognized by MDA5 [45] 2013 Antibodies in camels to Middle East respiratory syndrome coronavirus indicate widespread infection [44] 2013
The deubiquitinase activity of PLP2 from arterivirus inhibits innate immune signaling [47] 2014 Enteroviruses repress transcription of IFN genes through cleavage of MDA5 and MAVS [46] deal with both host and pathogen for a paper to be included. To develop the lists of major contributions to immunological progress (depicted in Tables 1-4), we had several brainstorms, interviews, and performed searches in PubMed. This led to a long list of Dutch scientists that were felt to have significantly contributed to the understanding of the immunology of infection, thereby focussing on research that was also performed in The Netherlands. Our next step was to contact these people and ask them to provide us with no more than 3 of their most contributory publications. With this information, using the premises formulated above, we were able to construct the tables below. We chose not to go for a bibliometric approach for a number of reasons. First of all, the bibliometrics in this field appears to be flawed by rather arbitrary listing in one of the following fields: immunology, microbiology, infectious diseases, public health, and medicine. Secondly, the real impact of articles is often difficult to assess. A certain idea or concept may not be readily taken up, or even may be captured by others. Also the publication habits have profoundly changed over the past decades. When we had gathered the articles that we wanted to include in this review, an important dilemma was how to order these contributions. We decided not to use an historical order, neither did we opt for investigators, groups or institutions, because mobility of investigators, contributions spanning many years, collaborations between institutions would lead to a distorted representation. So finally we decided to choose the order according to the major microorganism studied.
In Table 1 , contributions to host and virus interactions are presented. Dutch scientists were highly active immediately after the emergence of AIDS. This was possible because of the infrastructure created by the public health epidemiologist Roel Coutinho and the virologist Jan van der Noordaa. They facilitated the work of Goudsmit, Miedema, Lange and Schuitemaker, as described in Table 1 . The effects of antigenic variation, the non-protective antibody responses and the dynamics of the T cell compartment were described by these investigators [4] [5] [6] [7] [8] [9] [10] [11] [12] . Other important contributions have been made at the level of receptors that mediate HIV transmission to either dendritic cells (DCs) or T cells [13] [14] [15] . Table 2 Host/bacterium interaction.
Year Findings Reference
Staphylococcus 1979 Intracellular killing of bacteria by monocytes requires extracellular Igs and complement [51] 1983 Differential role of monocytes and granulocytes during course of Staphylococcus endocarditis [52] 1990 Bacterial iron contributes to oxidative killing of S. aureus [53] 1996 The complex clinical course of S. aureus bacteremia is not due to a relative lack of specific opsonins [130] 2005 Staphylococcal complement inhibitor decreases bacterial phagocytosis and killing by neutrophils [55] 2009 Staphylococcal SSL5 is immunomodulatory by targeting several stages of leukocyte extravasation [56] 2013
Staphylococcal toxin leukocidin targets C5a receptors, thereby regulating bacterial virulence [57] Neisseria 1992
The T cell repertoire against meningococcal OMP is more diverse than assumed [65] 1994 Fulminant meningococcal sepsis is associated with downregulated ex vivo cytokine production [60] 1997 The cytokine response in meningococcal sepsis soon turns into an anti-inflammatory repertoire [61] 1997 A genetically determined anti-inflammatory cytokine profile contributes to fatal meningococcal disease [62] 1998 Description of a Neisseria meningitidis mutant that can survive without lipopolysaccharide [58] 1999 Genetic predisposition to produce high PAI-1 levels impairs outcome of meningococcal sepsis [63] 2009
Natural mutant of Neisseria meningitidis with altered LPS form has low TLR4-activating capacity [59] 2010 Susceptibility to meningococcal disease depends on genetic variation in complement regulators [64] Mycobacterium 1976 Host response to Mycobacterium leprae is controlled by at least two HLA-linked genes [66] 1986 First identification of protein antigens from M. leprae that can activate specific CD4 T cells [67] 1993 Major antigenic epitopes from M. leprae are differentially expressed in leprosy lesions [68] Sugar-specific signaling through DC-SIGN shapes immunity to viruses and bacteria [15] Gut flora
Intestinal microflora has a strong impact on allogeneic lymphocyte responses in GVHD [81]
Resident intestinal microflora plays a role in the occurrence of GvHD [82,83] 2001 Immune status of mother and pup controls bacterial colonization in neonates [84] 2010
Microbiota composition in the gut is highly dependent on presence of enteric defensins [85] Sepsis/endotoxins 1988 Circulating endotoxins as good predictors of septicaemia in patients with bacterial infection [86] 1988 Low dose IL-1 enhances survival of Pseudomonas infection in neutropenic mice [87] 1989 IL-6 levels are increased in septic patients and correlate with disease severity [88] 1990 Single injection of recombinant TNF␣ is sufficient to cause activation of the coagulation system [89] 1990 Thorough analysis of innate immune responses upon experimental endotoxemia in humans [93] 1993 BPI is expressed on the surface of the granulocyte [54] 1996 Reconstituted high-density lipoprotein has anti-inflammatory effects during endotoxemia [95] 1996 Epinephrine inhibits TNF␣ release and enhances IL-10 production upon endotoxin challenge [94] 1998 High IL-10/TNF ratio is associated with mortality in community acquired infection [90] Both ROS-dependent and ROS-independent killing mechanism of C. albicans by neutrophils [104] Cryptococcus 2004 VEGF produced in cryptococcal meningitis may lead to blood-brain barrier disruption [109] Schistosoma-induced IL-10 production correlates with lower occurrence of atopy in children [122] 2010
Immune responses to BCG and P. falciparum are suppressed by worm-induced regulatory T cells [120] 2012
Schistosoma-derived Omega-1 induces Th2-mediated responses via dendritic cells [123] Other 1976
Intestinal mast cell response following Trichinella spiralis infection is dependent on T cells [124] 1994 Adaptive immune responses to Leishmania infantum correlate with disease progression in dogs [125] Another virus that has been studied by several Dutch research groups is Influenza A. This work ranges from the cellular and molecular mechanisms that drive protective anti-viral immunity [16] [17] [18] [19] [20] [21] , to the development of human antibodies with broadly neutralizing capacity against the virus [22, 23] . Investigation into the cellular anti-viral response encompassed the polyclonality of the responding T cell pool, the role of T cell co-stimulation and the formation of memory T cells, but also the involvement of innate immune cells their contribution to pathology [16, [18] [19] [20] 24] . Moreover, it has been shown that the inhibitory receptor CD200R plays an important role in diminishing immune pathology during influenza [25, 26] . Many approaches to study the immune response to influenza relied on the mouse as experimental model [16, 19, 21, [24] [25] [26] , but several groups have also been able to perform their analysis on human cells and tissues [17, 18, 27] .
Analysis of anti-viral responses directly in humans is of great value and has also been done for latent viruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) by several Dutch groups, which has revealed the great importance of our adaptive immune system to keep these infections in check [28] [29] [30] [31] . Identification of several specific strategies of EBV has provided insight into the molecular details on how this virus is able to evade the immune system and establish latency [32] [33] [34] [35] . Moreover, important contributions have also been made at the level of persistent infection with human papillomavirus (HPV), which is key for the development of cervical cancer: human T cell epitopes from HPV have been identified and shown to be effective in peptide vaccination to HPV [36] [37] [38] , which can subsequently induce remission of HPV-induced cervical lesions in patients [39, 40] . This has resulted in the decision of the Dutch government in 2010 to add HPV-vaccination for 12-year-old girls to the existing national immunization program.
Other Dutch contributions to anti-viral immunity have been made with vaccinia virus [41] , measles [42] , SARS [43] and MERS [44] , but also at the level of intracellular recognition of viruses [45] , viral dysregulation of innate sensing/interferon responses [46, 47] and how interferon-gamma production upon viral infection regulates hematopoiesis [48] [49] [50] .
The defence of the host against bacterial pathogens has been an intensive area of investigations in The Netherlands (Table 2) . At the side of the host, the function of phagocytic cells (granulocytes and mononuclear phagocytes) was investigated in different groups since the 1970s. The relevance of oxidative and nonoxidative bactericidal mechanisms, the importance of monocytes and macrophages, the activation of phagocytic cells were topics in many papers [51] [52] [53] [54] . Since the 1980s, the role of cytokines in the inflammatory response toward bacterial pathogens also became an important topic. Looking from the site of the bacterium, Staphylococcus aureus and especially its serious virulence and immune evasion have been intensively studied [55] [56] [57] .
Because of the high prevalence of serious meningococcal infection (especially serotype B) in The Netherlands at the end of the last century, several groups performed research to elucidate the interaction between this pathogen and the host. These studies yielded important insights in the role of the Neisserial endotoxin [58, 59] , the overwhelming inflammatory response and its subsequent downregulation (nowadays indicated as 'immune paralysis') [60, 61] , the genetic background of susceptibility [62] [63] [64] and in the adaptive immune response, relevant for vaccine development [65] .
Much work has been done on the interaction between mycobacteria (Mycobacterium leprae and Mycobacterium tuberculosis) and the immune system [15, [66] [67] [68] [69] [70] [71] [72] [73] . The role of HLA and T-cell recognition in leprosy [66, 67] , the interaction of M. tuberculosis with DC-SIGN [15, 71] and the role of cytokines and their receptors in susceptibility [70] are among the major findings. Other bacteria that have been the subject of Dutch research in immunology are Salmonella spp. [70, [74] [75] [76] , Bordetella pertussis [77, 78] and Helicobacter pylori [15, 79, 80] .
Pioneering work on the gastrointestinal flora and the induction of graft versus host disease was done by Van Bekkum and Van der Waaij in the 1970s and 1980s [81] [82] [83] . Later on, it was shown by the Bos group that bacterial colonization in neonates is controlled by the immune status of both mother and pup [84] , and that enteric defensins also play a critical role in this process [85] .
Parallel to the work on meningococcal sepsis, a large amount of studies was published on bacterial sepsis, the role of endotoxin and of potential interventions [86] [87] [88] [89] [90] [91] [92] . Important insights in the pathophysiology of sepsis were obtained in the experimental endotoxemia in human volunteers [93] [94] [95] [96] [97] [98] .
With regard to genetic susceptibility to infection, an early elegant study was done by De Vries and Van Rood; they convincingly showed that severe infections in humans causes natural selection of certain HLA types [99] . Nearly 30 years later similar effects were shown for TLR4 polymorphisms during human migration by Netea et al. [100] . Genetic susceptibility to infection was also studied for specific pathogens such as meningococci [62] [63] [64] , pneumococci [101] , mycobacteria [66, 70] and Salmonella species [70, 74] .
Studies on host defence against the major fungal pathogen Candida albicans started in the 1980s, in an era when disseminated infections with this opportunistic pathogen became more prevalent in The Netherlands. These invasive infections were especially prominent in patients with neutropenia and those with neutrophil dysfunction disorders, and hence it was obvious to initiate studies on the role of phagocytic cells, i.e., granulocytes and monocytes [102] .
An intriguing group of patients with undue susceptibility to Candida species, as well as to dermatophytes, are patients with chronic mucocutaneous candidiasis. The elucidation of the defect in these patients, specifically with the autosomal dominant form, would take until 2011, with the discovery that mutations of the STAT1 gene are responsible for a large proportion of these patients [103] . The defective subsequent production of interferons, IL-17, IL-23, leading to insufficient neutrophil activation and defensin production are considered to lead to the susceptibility to the fungal pathogens. In depth analysis of the fungicidal capacity of human neutrophils revealed that these cells can use two distinct and independent phagolysosomal mechanisms to kill C. albicans, being either reactive oxygen species-dependent when mediated by Fc␥ receptors or reactive-oxygen species independent when mediated through complement receptor 3 and CARD-9 [104] . A thoroughly studied topic is that of recognition of Candida species by host cells. A series of molecular patterns on the surface of the fungus was identified as ligands for an array of pattern-recognition receptors [105, 106] . On the other hand, the tetraspanin CD37 was found to inhibit IgA responses to Candida and thereby able to regulate the anti-fungal immune response [107] . In 2012, a new paradigm, 'trained immunity' was put forward by Netea's group, based on the observation that beta-glucan derived from Candida (and muramyl dipeptide from BCG) is able to enhance the innate immune effector function through epigenetic reprogramming of monocytes and macrophages [108] .
The immunity to other fungal pathogens, Cryptococcus neoformans and Aspergillus species has also been studied. Here we mention the effect of C. neoformans on the production in the cerebrospinal fluid of VEGF, which is thought to be important in the disruption of the blood-brain barrier [109] .
Seminal studies on the interaction between the host and Trypanosoma bruzei were performed by Borst and his group, demonstrating for the first time the incredible antigenic versatility of this parasite [110] [111] [112] . The parasite genome contains some 1000 genes encoding the variant surface glycoproteins, rendering vaccine development a futile undertaking.
Most of the work on parasites in Dutch immunology concerns malaria parasites. Meuwissen's group was the first to show the sequential appearance of antigens on the sexual stages of Plasmodium falciparum, the cause of tropical malaria [113] . This work formed the basis for development of transmission blocking vaccines. Another seminal study at that time dealt with the early liver form of the plasmodia [114] . Other Dutch research on malaria dealt with the technology to genetically modify and attenuate malaria parasites, in order to use these for immunization [115] [116] [117] . Another major advance in malaria research was obtained in the experimental malaria studies in human volunteers. Using this set up, pre-erythrocytic immunity was obtained by inoculating the volunteers with live P. falciparum sporozoites under chloroquine treatment, and the investigators were able to demonstrate long-lasting protection against a malaria challenge [118, 119] .
Intestinal helminth infestations, which are endemic in many non-western societies, appear to affect on the immune system of the host. Yazdanbakhsh and her group have performed many studies to assess these immunomodulatory effects in more detail. They demonstrated that regulatory T cells induced by these worms suppress the T cell response to plasmodia-parasitised erythrocytes and to BCG [120] . This work builds on earlier work, in which T-cell hyporeponsiveness induced by schistosoma infection was shown [121] . Induction of IL-10 by the schistosomes appeared to be an important effector mechanism [122] . The major schistosoma egg antigen Omega-1 was shown to induce Th2 polarization through ligation of the mannose receptor on dendritic cells [123] .
Seminal work by Ruitenberg revealed that the increase of intestinal mast cells observed during the intestinal phase of infection with the nematode Trichinella spiralis is highly dependent on T cells, as it does not occur in athymic (nude) mice [124] . Interestingly, parasite infections were found to have even long-lasting effects on the immune system, as dogs infected with leishmania 3 years later greatly differed in the immune response according to their disease manifestations: asymptomatic dogs had a strong cellular immune response (with high IL-2 and TNF␣ production) while symptomatic dogs exhibited a mere antibody response [125] .
In the present review we have attempted to cover nearly 50 years of Dutch immunological studies in the area of infectious diseases. Although we have tried to be complete, we are pretty sure that we have overlooked some important contributions. Moreover, because of the nature of this review, some topics and teams of scientists will have been more highlighted than others. For this we apologize. It is clear from the review that the scientists in The Netherlands that were and are active in this area have produced articles that had and still have quite an impact on the way we view host and pathogen interaction nowadays. It is interesting to see that -although there are areas with quite a large number of contributions (such as those on immunity to HIV, influenza virus, S. aureus, sepsis, endotoxin and malaria), there are important contributions dealing with many other infectious agents. It is also clear that the field is more active than ever before, and that we will see great future Dutch scientific contributions in this fascinating area.
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