SNPs in innate immune genes are important in determining susceptibility to RSV bronchiolitis.

SUMMARY Campylobacter is a major cause of acute bacterial diarrhea in humans worldwide. This study was aimed at summarizing the current understanding of host mechanisms involved in the defense against Campylobacter by evaluating data available from three sources: (i) epidemiological observations, (ii) observations of patients, and (iii) experimental observations including observations of animal models and human volunteer studies. Analysis of available data clearly indicates that an effective immune system is crucial for the host defense against Campylobacter infection. Innate, cell-mediated, and humoral immune responses are induced during Campylobacter infection, but the relative importance of these mechanisms in conferring protective immunity against reinfection is unclear. Frequent exposure to Campylobacter does lead to the induction of short-term protection against disease but most probably not against colonization. Recent progress in the development of more suitable animal models for studying Campylobacter infection has opened up possibilities to study the importance of innate and adaptive immunity during infection and in protection against reinfection. In addition, advances in genomics and proteomics technologies will enable more detailed molecular studies. Such studies combined with better integration of host and pathogen research driven by epidemiological findings may truly advance our understanding of Campylobacter infection in humans.

Both innate and adaptive immune responses are dependent on activation of nuclear factor κB (NF-κB), induced upon binding of pathogen-associated molecular patterns to Toll-like receptors (TLRs). In murine models, defects in NF-κB pathway are often lethal and viable knockout mice have severe immune defects. Similarly, defects in the human NF-κB pathway described to date lead to severe clinical disease. Here, we describe a patient with a hyper immunoglobulin M–like immunodeficiency syndrome and ectodermal dysplasia. Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-κB was impaired. T cell receptor–mediated proliferation was also impaired. A heterozygous mutation was found at serine 32 in IκBα. Interestingly, his father has the same mutation but displays complex mosaicism. He does not display features of ectodermal dysplasia and did not suffer from serious infections with the exception of a relapsing Salmonella typhimurium infection. His monocyte function was impaired, whereas T cell function was relatively normal. Consistent with this, his T cells almost exclusively displayed the wild-type allele, whereas both alleles were present in his monocytes. We propose that the T and B cell compartment of the mosaic father arose as a result of selection of wild-type cells and that this underlies the widely different clinical phenotype.

Following uptake by macrophages, live mycobacteria initially reside within an immature phagosome that resists acidification and retains access to recycling endosomes. Glycolipids are exported from the mycobacterial phagosome and become available for immune recognition by CD1-restricted T cells. The aim of this study was to explore the possibility that lipoproteins might similarly escape from the phagosome and act as immune targets in cells infected with live mycobacteria. We have focused on a 19-kDa lipoprotein from Mycobacterium tuberculosis that was previously shown to be recognized by CD8+ T cells. The 19-kDa Ag was found to traffic separately from live mycobacteria within infected macrophages by a pathway that was dependent on acylation of the protein. When expressed as a recombinant protein in rapid-growing mycobacteria, the 19-kDa Ag was able to deliver peptides for recognition by MHC class I-restricted T cells by a TAP-independent mechanism. Entry into the class I pathway was rapid, dependent on acylation, and could be blocked by killing the mycobacteria by heating before infection. Although the pattern of 19-kDa trafficking was similar with different mycobacterial species, preliminary experiments suggest that class I presentation is more efficient during infection with rapid-growing mycobacteria than with the slow-growing bacillus Calmette-Guérin vaccine strain.

Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infection in children.Severe RSV disease is related to an inappropriate immune response to RSV resulting in enhanced lung pathology which is influenced by host genetic factors. To gain insight into the early pathways of the pathogenesis of and immune response to RSV infection, we determined the transcription profiles of lungs and lymph nodes on days 1 and 3 after infection of mice. Primary RSV infection resulted in a rapid but transient innate, proinflammatory response, as exemplified by the induction of a large number of type I interferon-regulated genes and chemokine genes, genes involved in inflammation, and genes involved in antigen processing. Interestingly, this response is much stronger on day 1 than on day 3 after infection, indicating that the strong transcriptional response in the lung precedes the peak of viral replication. Surprisingly, the set of downregulated genes was small and none of these genes displayed strong down-regulation. Responses in the lung-draining lymph nodes were much less prominent than lung responses and are suggestive of NK cell activation. Our data indicate that at time points prior to the peak of viral replication and influx of inflammatory cells, the local lung response, measured at the transcriptional level, has already dampened down. The processes and pathways induced shortly after RSV infection can now be used for the selection of candidate genes for human genetic studies of children with severe RSV infection.The severity of respiratory syncytial virus (RSV) infection in young children varies from a nonclinical or mild upper respiratory tract infection to severe lower respiratory tract infection that may lead to hospitalization and occasionally to death. Some children are more prone to a severe course of disease, such as premature-born children, children younger than 3 months of age, children with chronic lung disease or congenital heart disease, and immunocompromised children (27,35). However, the biological mechanisms underlying the highly variable disease course in children are still poorly understood. The current belief is that children with severe RSV disease suffer from enhanced inflammatory lesions rather than from virus-induced cytopathology (25). In line with this, naturally occurring polymorphisms in genes affecting the inflammatory immune response influence the severity of RSV-induced disease (5,11,12,15).Immune responses to viral pathogens are initiated among others via the recognition of pathogen-associated molecular patterns by various Toll-like receptors (TLR), leading to the induction of innate immune responses, proinflammatory cytokines, and the Th1 pathway (reviewed in references 18 and 26). Innate immunity to RNA viruses is initiated by TLR3 and murine TLR7 or human TLR8, which are important for the responses to double-stranded and single-stranded RNAs, and through intracellular RNA recognition molecules, such as RIG-I and Mda5 (reviewed in reference 21). Both TLR3 and R...

Patients with defects in IFN-γ- or IL-12-mediated immunity are susceptible to infections with Salmonella and non-tuberculous mycobacteria, but rarely suffer from infections with other intracellular pathogens such as Toxoplasma gondii. Here we describe macrophage and T cell function in eight individuals with partial IFN-γ receptor 1 (IFN-γR1) deficiency due to a mutation that results in elevated cell surface expression of a truncated IFN-γR1 receptor that lacks the intracellular domain. We show that various effector mechanisms dependent on IFN-γR signaling are affected to different extents. Whereas TNF-α production was normally up-regulated in response to IFN-γ, IL-12 production and CD64 up-regulation were strongly reduced, and IFN-γ-mediated killing of the intracellular pathogens Salmonella typhimurium and T. gondii was completely abrogated in patient’s macrophages. Since these patients suffer selectively from infections with non-tuberculous mycobacteria and Salmonella, but not T. gondii, despite sero-immunity in six of eight patients, which indicates previous contact with this pathogen, we next studied the role of TNF-α as a possible immune compensatory mechanism. IFN-γ-induced killing of T. gondii appeared to be partially mediated by TNF-α, and addition of TNF-α could compensate for the abrogated killing of T. gondii in the patient’s macrophages. In contrast, IFN-γ-mediated killing of S. typhimurium appeared to be independent of TNF-α. We propose that the divergent role of TNF-α in IFN-γ-induced killing of T. gondii and S. typhimurium may at least partially explain the highly selective susceptibility of patients.

Respiratory syncytial virus is a leading cause of lower respiratory tract infection in infants. Disease severity has been linked to host immune responses and polymorphisms in genes associated with innate immunity. A large‐scale genetics study of single nucleotide polymorphisms (SNPs) in children in the Netherlands identified SNPs in the vitamin D receptor (VDR) and JUN genes which have a strong association with an increased risk of developing bronchiolitis following the first respiratory syncytial virus (RSV) infection. The Toll‐like receptor 4 (TLR4) gene has two SNPs which have been associated previously with RSV disease severity in various populations. The aim of this study was to determine if these SNPs may be associated with RSV disease in African children in South Africa. RSV patient (n = 296) and control (n = 113) groups were established (median ages: 3 and 3.5 months) and DNA extracted from the collected specimens. Real‐time polymerase chain reaction using hydrolysis probes was used to screen for SNPs in the VDR (Thr1Meth; rs10735810), TLR4 (Asp299Gly; rs4986790 and Thr399Ile; rs4986791) and JUN (c.750G/A; rs11688) genes. Carriers of the VDR (Thr1Meth) SNP minor T allele were more prone to RSV disease than individuals in the control group. The TLR4 (Asp299Gly), TLR4 (Thr399Ile), and JUN (c.750G/A) SNPs showed no significant association with RSV disease. It is concluded that children carrying the minor T allele of the VDR (Thr1Meth) SNP may be predisposed to RSV disease, as this SNP was identified as a risk factor for severe RSV disease in South African children, confirming the findings in the Netherlands. J. Med. Virol. 83:1834–1840, 2011. © 2011 Wiley‐Liss, Inc.

This report confirms the essential role of STAT5b in GH signaling in the human. We show for the first time that immunological or pulmonary problems or elevated GH secretion are not obligatory signs of STAT5b deficiency, whereas hyperprolactinemia appears to be part of the syndrome. Therefore, in patients with severe short stature, signs of GH insensitivity, and a normal GHR, analysis of the STAT5b gene is recommended.