Zika virus encephalitis in immunocompetent mice is dominated by innate immune cells and does not require T or B cells

Abstract Background Until the end of the twentieth century, Zika virus (ZIKV) was thought to cause a mostly mild, self-limiting disease in humans. However, as the geographic distribution of ZIKV has shifted, so too has its pathogenicity. Modern-day ZIKV infection is now known to cause encephalitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome in otherwise healthy adults. Nevertheless, the underlying pathogenetic mechanisms responsible for this shift in virulence remain unclear. Methods Here, we investigated the contribution of the innate versus the adaptive immune response using a new mouse model involving intracranial infection of adult immunocompetent mice with a moderately low dose of ZIKV MR766. To determine the contribution of type I interferons (IFN-Is) and adaptive immune cells, we also studied mice deficient for the IFN-I receptor 1 (Ifnar1−/−) and recombination-activating gene 1 (Rag1−/−). Results We show that intracranial infection with ZIKV resulted in lethal encephalitis. In wild-type mice, ZIKV remained restricted predominantly to the central nervous system (CNS) and infected neurons, whereas astrocytes and microglia were spared. Histological and molecular analysis revealed prominent activation of resident microglia and infiltrating monocytes that were accompanied by an expression of pro-inflammatory cytokines. The disease was independent of T and B cells. Importantly, unlike peripheral infection, IFN-Is modulated but did not protect from infection and lethal disease. Lack of IFN-I signaling resulted in spread of the virus, generalized inflammatory changes, and accelerated disease onset. Conclusions Using intracranial infection of immunocompetent wild-type mice with ZIKV, we demonstrate that in contrast to the peripheral immune system, the CNS is susceptible to infection and responds to ZIKV by initiating an antiviral immune response. This response is dominated by resident microglia and infiltrating monocytes and macrophages but does not require T or B cells. Unlike in the periphery, IFN-Is in the CNS cannot prevent the establishment of infection. Our findings show that ZIKV encephalitis in mice is dependent on the innate immune response, and adaptive immune cells play at most a minor role in disease pathogenesis.

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Maternal Adaptive Immune Cells in Decidua Parietalis Display a More Activated and Coinhibitory Phenotype Compared to Decidua Basalis

Stem Cells International ◽

10.1155/2017/8010961 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Martin Solders ◽

Laia Gorchs ◽

Sebastian Gidlöf ◽

Eleonor Tiblad ◽

Anna-Carin Lundell ◽

...

Keyword(s):

B Cells ◽

Immune Cells ◽

T Regulatory Cells ◽

Mait Cells ◽

Adaptive Immune ◽

Cell Compartments ◽

Decidua Basalis ◽

Adaptive Immune Cells ◽

Cytotoxic Molecules ◽

Multivariate Discriminant

The maternal part of the placenta, the decidua, consists of maternal immune cells, decidual stromal cells, and extravillous fetal trophoblasts. In a successful pregnancy, these cell compartments interact to provide an intricate balance between fetal tolerance and antimicrobial defense. These processes are still poorly characterized in the two anatomically different decidual tissues, basalis and parietalis. We examined immune cells from decidua basalis and parietalis from term placentas (n=15) with flow cytometry. By using multivariate discriminant analysis, we found a clear separation between the two decidual compartments based on the 81 investigated parameters. Decidua parietalis lymphocytes displayed a more activated phenotype with a higher expression of coinhibitory markers than those isolated from basalis and contained higher frequencies of T regulatory cells. Decidua basalis contained higher proportions of monocytes, B cells, and mucosal-associated invariant T (MAIT) cells. The basalis B cells were more immature, and parietalis MAIT cells showed a more activated phenotype. Conventional T cells, NK cells, and MAIT cells from both compartments potently responded with the production of interferon-γand/or cytotoxic molecules in response to stimulation. To conclude, leukocytes in decidua basalis and parietalis displayed remarkable phenotypic disparities, indicating that the corresponding stromal microenvironments provide different immunoregulatory signals.

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B-1a B Cells that Link the Innate and Adaptive Immune Responses Are Lacking in the Absence of the Spleen

Journal of Experimental Medicine ◽

10.1084/jem.20011140 ◽

2002 ◽

Vol 195 (6) ◽

pp. 771-780 ◽

Cited By ~ 185

Author(s):

Hedda Wardemann ◽

Thomas Boehm ◽

Neil Dear ◽

Rita Carsetti

Keyword(s):

B Cells ◽

Immune Responses ◽

B Cell ◽

Innate Immune ◽

Streptococcal Infections ◽

Wild Type ◽

Adaptive Immune ◽

Encapsulated Bacteria ◽

Increased Susceptibility

Splenectomized individuals are prone to overwhelming infections with encapsulated bacteria and splenectomy of mice increases susceptibility to streptococcal infections, yet the exact mechanism by which the spleen protects against such infections is unknown. Using congenitally asplenic mice as a model, we show that the spleen is essential for the generation of B-1a cells, a B cell population that cooperates with the innate immune system to control early bacterial and viral growth. Splenectomy of wild-type mice further demonstrated that the spleen is also important for the survival of B-1a cells. Transfer experiments demonstrate that lack of these cells, as opposed to the absence of the spleen per se, is associated with an inability to mount a rapid immune response against streptococcal polysaccharides. Thus, absence of the spleen and the associated increased susceptibility to streptococcal infections is correlated with lack of B-1a B cells. These findings reveal a hitherto unknown role of the spleen in generating and maintaining the B-1a B cell pool.

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The Maternal Immune Response to in Utero Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.64.64 ◽

2009 ◽

Vol 114 (22) ◽

pp. 64-64

Author(s):

Tippi MacKenzie ◽

Erin Jarvis ◽

Amar Nijagal ◽

Tom Le ◽

Marta Wegorzewska ◽

...

Keyword(s):

Immune Response ◽

Stem Cell ◽

Immune System ◽

B Cells ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

In Utero ◽

Wild Type ◽

Hematopoietic Stem ◽

Adaptive Immune

Abstract Abstract 64 In utero hematopoietic stem cell transplantation (IUHSCTx) is a promising treatment strategy for many congenital hematopoietic disorders such as immunodeficiencies. However, clinical applications have been hampered by lack of engraftment, possibly secondary to a host immune response. This has been a conundrum in the field, since the fetus can also be tolerized to allogeneic cells in some circumstances. We hypothesized that it is the maternal immune response which limits engraftment of in utero transplanted cells. Methods: Fetal BALB/c mice at 14 days' gestation were transplanted with age-matched fetal liver (FL) cells (2.5 × 106 cells/fetus) from allogeneic C57B6 mice and levels of circulating donor cell chimerism were determined serially starting at 4 weeks after in utero transplantation. Rates of engraftment (number of chimeric pups/number of surviving pups) and levels of chimerism (donor CD45 cells/total CD45 cells) were compared to controls in which animals were transplanted with congenic cells (C57B6 (CD45.2) fetal hosts transplanted with C57B6 (CD45.1) FL). In order to determine the role of the maternal adaptive immune system, immunodeficient BALB/c.Rag−/− mothers (deficient in T and B cells) were bred to wild type BALB/c males, such that the fetuses (BALB/c.Rag+/−) would be immunocompetent. These fetuses were transplanted with C57B6 FL and rates of engraftment and levels of chimerism in these transplants were compared to those in wild type allogeneic transplants. In order to determine whether the maternal influence is caused by maternal lymphocytes trafficking into the fetus, C57B6 (CD45.2) females were bred to C57B6 (CD45.1) males, such that the fetal cells (CD45.1+/CD45.2+) could be distinguished from maternal cells (CD45.1−/CD45.2+). Fetal blood and tissues were examined for the presence of maternal cells by flow cytometry at various gestational ages. Results: The rate of engraftment after IUHSCTx in control animals transplanted with congenic cells was 14/16 (88%) and average levels of chimerism were 9.9±8.4%. In contrast, the rate of engraftment in wild-type BALB/c fetuses transplanted with allogeneic B6 cells was 11/25 (44%; p<0.05 compared to congenic), and levels of chimerism were 21±19 (p=NS), confirming there is an adaptive immune response to fetal stem cell transplantation. As expected, chimeric animals were tolerant to the donor strain by mixed lymphocyte reaction while injected, non-chimeric animals were sensitized. However, in the absence of a maternal adaptive immune system, rates of chimerism (in immunocompetent BALB/c.Rag+/− pups) increased to 100% (n=10, p<0.05 compared to wild type allogeneic) and levels of chimerism were significantly higher (44±18, p<0.05). Levels of chimerism in engrafted animals declined over time after allogeneic transplantation but not after congenic transplantation, indicating there is a second, late phase immune response to allogeneic cells. However, chimerism levels did not decline in the BALB/c.Rag+/− recipients, suggesting that the maternal immune system has long-lasting effects on the success of fetal transplantation, perhaps by priming the host immune system. In our analysis of maternal/fetal cellular trafficking, we detected maternal lymphocytes in the blood of midgestation fetuses (14±7% at E12.5–E14.5, n=9) which declined gradually and was undetectable after birth. Lineage analysis demonstrated that 45±15 % of maternal cells are Gr-1+ granulocytes and 21±15% are B cells. Trafficking of maternal cells into the fetus was increased following fetal manipulation (injection of PBS < injection of allogeneic HSC). Conclusions: There is an adaptive immune response which limits early engraftment after in utero transplantation of allogeneic cells and leads to a gradual decline in levels of chimerism in engrafted animals. However, in the selective absence of maternal T and B cells, all fetuses transplanted with allogeneic FL cells show long-term, multilineage engraftment and demonstrate donor-specific tolerance. These results indicate that the maternal immune system plays a significant role in the success of fetal HSC transplantation. Cellular trafficking between the mother and fetus may be a mechanism by which maternal lymphocytes encounter cells transplanted into the fetus. Our findings have clinical implications in that the success of IUHSCTx may be improved by harvesting cells from the mother or HLA-matching cells to the mother. Disclosures: No relevant conflicts of interest to declare.

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Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

10.1101/248807 ◽

2018 ◽

Author(s):

Carlos R. Figueiredo ◽

Ricardo A. Azevedo ◽

Sasha Mousdell ◽

Pedro T. Resende-Lara ◽

Lucy Ireland ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Metastatic Melanoma ◽

Immune Cells ◽

Tumour Microenvironment ◽

Innate Immune ◽

Innate Immune Cells ◽

Adaptive Immune Cells ◽

Cancer Immunotherapies

ABSTRACTMounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells’ immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

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Adaptive Immune Response to Shigella flexneri 2acydC in Immunocompetent Mice and Mice Lacking Immunoglobulin A

Infection and Immunity ◽

10.1128/iai.67.4.2001-2004.1999 ◽

1999 ◽

Vol 67 (4) ◽

pp. 2001-2004 ◽

Cited By ~ 20

Author(s):

Sing Sing Way ◽

Alain C. Borczuk ◽

Marcia B. Goldberg

Keyword(s):

Immune Response ◽

Adaptive Immunity ◽

Shigella Flexneri ◽

Immunoglobulin A ◽

Adaptive Immune Response ◽

Model System ◽

Wild Type ◽

Adaptive Immune ◽

Immunocompetent Mice

ABSTRACT Shigella flexneri cydC, which is deficient in cytochrome bd, was rapidly cleared from the lungs of intranasally inoculated mice and was Sereny negative, yet it induced 93% protection against challenge with wild-type S. flexneri. Mice that lack immunoglobulin A (IgA) were fully protected, suggesting that IgA may not be required for adaptive immunity in this model system.

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Immune Response to SARS-CoV-2 Infection

International Journal of Current Science Research and Review ◽

10.47191/ijcsrr/v3-i10-03 ◽

2020 ◽

Vol 03 (10) ◽

Author(s):

Dr. Ahmed Al-Shukaili ◽

Keyword(s):

Immune Response ◽

Immune System ◽

Severe Acute Respiratory Syndrome ◽

Global Health ◽

Immune Cells ◽

Current Knowledge ◽

Adaptive Immune ◽

Proinflammatory Mediators ◽

Adaptive Immune Cells ◽

New Type

In December 2019 a new type of coronaviruses appeared in China and named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the disease associated with this virus is called Coronavirus Disease 2019 or COVID-19. Currently, COVID19 is the main global health threat. In this review, we focus in the current knowledge of immune response to SARS-CoV-2. Dysregulation of immune system, such as elevation levels of proinflammatory mediators and their roles in disease progression and pathogenesis as well as imbalance between innate and adaptive immune cells, are discussed in this review.

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Basic Immunology

Tutorial Topics in Infection for the Combined Infection Training Programme ◽

10.1093/oso/9780198801740.003.0012 ◽

2019 ◽

Author(s):

Jonathan Lambourne ◽

Ruaridh Buchanan

Keyword(s):

Immune Response ◽

Immune System ◽

Epithelial Cells ◽

Immune Cells ◽

Innate Immune System ◽

Adaptive Immune System ◽

Lymphoid Organs ◽

Innate Immune ◽

Adaptive Immune ◽

Pathogen Entry

There are four major components of the immune system. These include: 1. mechanical barriers to pathogen entry. 2. the innate immune system. 3. the adaptive immune system. 4. the lymphoid organs. Mechanical barriers include skin and mucous membranes and tight junctions between epithelial cells prevent pathogen entry. Breaches can be iatrogenic, for example, IV lines, surgical wounds, and mucositis, and are a large source of healthcare- associated infections. The innate immune system provides the first internal line of defence, as well as initiating and shaping the adaptive immune response. The innate system comprises a range of responses: phagocytosis by neutrophils and macrophages (guided in part by the adaptive immune system), the complement cascade, and the release of antimicrobial peptides by epithelial cells (e.g. defensins, cathelicidin). The adaptive immune system includes both humoral (antibody- mediated) and cell-mediated responses. It is capable of greater diversity and specificity than the innate immune system, and can develop memory to pathogens and provide increased protection on re-exposure. Immune cells are divided into myeloid cells (neutrophils, eosinophils, basophils, mast cells, and monocytes/macrophages) and lymphoid cells (B, T, and NK cells). These all originate in the bone marrow from pluripotent haematopoietic stem cells. The lymphoid organs include the spleen, the lymph nodes, and mucosal-associated lymphoid tissues—which respond to antigens in the blood, tissues, and epithelial surfaces respectively. The three main ‘professional’ phagocytes are macrophages, dendritic cells, and neutrophils. They are similar with respect to how they recognize pathogens, but differ in their principal location and effector functions. Phagocytes express an array of Pattern Recognition Receptors (PRRs) e.g. Toll-like receptors and lectins (proteins that bind carbohydrates). PRRs recognize Pathogen- Associated Molecular Patterns (PAMPs)— elements which are conserved across species, such as cell-surface glycoproteins and nucleic acid sequences. Though limited in number, PRRs have evolved to recognize a huge array of pathogens. Binding of PRRs to PAMPs enhances phagocytosis. Macrophages are tissue-resident phagocytes, initiating and co-ordinating the local immune response. The cytokines and chemokines they produce cause vasodilation and alter the expression of endothelial cell adhesion factors, recruiting circulating immune cells.

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Abstract P024: Using innate immune ligands to activate adaptive immune cells for glioblastoma therapy

10.1158/2326-6074.tumimm21-p024 ◽

2022 ◽

Author(s):

Richard T. Baugh ◽

Hena Khalique ◽

Janet Lei-Rossmann ◽

Len Seymour

Keyword(s):

Immune Cells ◽

Innate Immune ◽

Adaptive Immune ◽

Adaptive Immune Cells

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The Infecting Dose of Chlamydia muridarum Modulates the Innate Immune Response and Ascending Infection

Infection and Immunity ◽

10.1128/iai.72.11.6330-6340.2004 ◽

2004 ◽

Vol 72 (11) ◽

pp. 6330-6340 ◽

Cited By ~ 46

Author(s):

Heather K. Maxion ◽

Wei Liu ◽

Mi-Hyang Chang ◽

Kathleen A. Kelly

Keyword(s):

Immune Response ◽

Immune Cells ◽

Genital Tract ◽

Bacterial Load ◽

Female Genital Tract ◽

Innate Immune ◽

Chlamydia Muridarum ◽

Cell Numbers ◽

Adaptive Immune ◽

Ascending Infection

ABSTRACT Murine vaginal infection with the obligate intracellular bacterium Chlamydia muridarum is commonly used as a model for ascending Chlamydia infections of the human female genital tract. Gamma interferon-producing Th1 cells, in concert with other mononuclear infiltrates, primarily mediate antichlamydial immunity. However, many factors modify this response, including the bacterial load. To investigate the manner in which the inoculating dose of C. muridarum modulates a genital infection, we measured innate and adaptive cell numbers, CD4+ lymphocyte cytokine profile, chemokine expression, course of infection, and pathological sequelae in genital tracts of BALB/c mice infected with doses of C. muridarum ranging from 104 to 107 inclusion-forming units. We found that the influx of both innate and adaptive immune cells responded similarly in the lower genital tract (cervical-vaginal tissues) and upper genital tract (oviduct tissues) to increasing inoculating doses. However, cells expressing the innate markers Gr-1 and CD11c were affected to a greater degree by increasing dose than lymphocytes of the adaptive immune response (Th1, CD4+, CD8+, CD19+), resulting in a change in the balance of innate and adaptive cell numbers to favor innate cells at higher infecting doses. Surprisingly, we detected greater numbers of viable chlamydiae in the oviducts at lower inoculating doses, and the number of organisms appeared to directly correlate with hydrosalpinx formation after both primary infection and repeat infection. Taken together, these data suggest that innate immune cells contribute to control of ascending infection.

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