Brain Immune Pathways Regulating Immunological Function and Conditioned Immune Responses

Plants harbor various beneficial bacteria that modulate their innate immunity, resulting in induced systemic resistance (ISR) against various pathogens. However, the immune mechanisms underlying ISR triggered by Bacillus spp. and Pseudomonas spp. against pathogens with different lifestyles are not yet clearly elucidated. Here, we show that root drenching of Arabidopsis plants with Pseudomonas fluorescensPTA-CT2 and Bacillus subtilis PTA-271 can induce ISR against the necrotrophic fungus B. cinerea and the hemibiotrophic bacterium Pseudomonas syringae Pst DC3000. In the absence of pathogen infection, both beneficial bacteria do not induce any consistent change in systemic immune responses. However, ISR relies on priming faster and robust expression of marker genes for the salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) signaling pathways upon pathogen challenge. These responses are also associated with increased levels of SA, JA, and abscisic acid (ABA) in the leaves of bacterized plants after infection. The functional study also points at priming of the JA/ET and NPR1-dependent defenses as prioritized immune pathways in ISR induced by both beneficial bacteria against B. cinerea. However, B. subtilis-triggered ISR against Pst DC3000 is dependent on SA, JA/ET, and NPR1 pathways, whereas P. fluorescens-induced ISR requires JA/ET and NPR1 signaling pathways. The use of ABA-insensitive mutants also pointed out the crucial role of ABA signaling, but not ABA concentration, along with JA/ET signaling in primed systemic immunity by beneficial bacteria against Pst DC3000, but not against B. cinerea. These results clearly indicate that ISR is linked to priming plants for enhanced common and distinct immune pathways depending on the beneficial strain and the pathogen lifestyle.

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Recent advances in understanding inherited deficiencies in immunity to infections

F1000Research ◽

10.12688/f1000research.22036.1 ◽

2020 ◽

Vol 9 ◽

pp. 243 ◽

Cited By ~ 1

Author(s):

Gregory M. Constantine ◽

Michail S. Lionakis

Keyword(s):

Immune Responses ◽

Host Defense ◽

Fungal Infections ◽

Microbial Pathogens ◽

Host Immune Responses ◽

Vaccination Strategies ◽

The World ◽

Human Immunity ◽

Immune Pathways ◽

Resistance To Infection

The immune system is central to our interactions with the world in which we live and importantly dictates our response to potential allergens, toxins, and pathogens to which we are constantly exposed. Understanding the mechanisms that underlie protective host immune responses against microbial pathogens is vital for the development of improved treatment and vaccination strategies against infections. To that end, inherited immunodeficiencies that manifest with susceptibility to bacterial, viral, and/or fungal infections have provided fundamental insights into the indispensable contribution of key immune pathways in host defense against various pathogens. In this mini-review, we summarize the findings from a series of recent publications in which inherited immunodeficiencies have helped illuminate the interplay of human immunity and resistance to infection.

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STING mediates immune responses in the closest living relatives of animals

eLife ◽

10.7554/elife.70436 ◽

2021 ◽

Vol 10 ◽

Author(s):

Arielle Woznica ◽

Ashwani Kumar ◽

Carolyn R Sturge ◽

Chao Xing ◽

Nicole King ◽

...

Keyword(s):

Immune Responses ◽

Model System ◽

Innate Immune ◽

Dependent Manner ◽

First Line ◽

Immune Genes ◽

Cyclic Dinucleotides ◽

Immune Pathways ◽

Innate Immune Genes ◽

Cyclic Dinucleotide

Animals have evolved unique repertoires of innate immune genes and pathways that provide their first line of defense against pathogens. To reconstruct the ancestry of animal innate immunity, we have developed the choanoflagellate Monosiga brevicollis, one of the closest living relatives of animals, as a model for studying mechanisms underlying pathogen recognition and immune response. We found that M. brevicollis is killed by exposure to Pseudomonas aeruginosa bacteria. Moreover, M. brevicollis expresses STING, which, in animals, activates innate immune pathways in response to cyclic dinucleotides during pathogen sensing. M. brevicollis STING increases the susceptibility of M. brevicollis to P. aeruginosa-induced cell death and is required for responding to the cyclic dinucleotide 2'3' cGAMP. Furthermore, similar to animals, autophagic signaling in M. brevicollis is induced by 2'3' cGAMP in a STING-dependent manner. This study provides evidence for a pre-animal role for STING in antibacterial immunity and establishes M. brevicollis as a model system for the study of immune responses.

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Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans

Journal of Experimental Medicine ◽

10.1084/jem.20111171 ◽

2011 ◽

Vol 208 (12) ◽

pp. 2357-2366 ◽

Cited By ~ 192

Author(s):

Marina Caskey ◽

François Lefebvre ◽

Abdelali Filali-Mouhim ◽

Mark J. Cameron ◽

Jean-Philippe Goulet ◽

...

Keyword(s):

Immune Responses ◽

Subcutaneous Administration ◽

Innate Immune ◽

Transcriptional Analysis ◽

Yellow Fever Vaccine ◽

Type I ◽

Innate Immune Responses ◽

Double Stranded Rna ◽

Viral Vaccine ◽

Immune Pathways

Adjuvants are critical for the success of vaccines. Agonists of microbial pattern recognition receptors (PRRs) are promising new adjuvant candidates. A mechanism through which adjuvants enhance immune responses is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double-stranded RNA (polyinosinic:polycytidylic acid [poly IC] stabilized with poly-l-lysine [poly ICLC]), an agonist for toll-like receptor (TLR) 3, and the cytosolic RNA helicase MDA-5. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC, showed up-regulation of genes involved in multiple innate immune pathways in all subjects, including interferon (IFN) and inflammasome signaling. Blocking type I IFN receptor ex vivo significantly dampened the response to poly IC. Comparative transcriptional analysis showed that several innate immune pathways were similarly induced in volunteers immunized with the highly efficacious yellow fever vaccine. Therefore, a chemically defined PRR agonist like poly ICLC can be a reliable and authentic microbial mimic for inducing innate immune responses in humans.

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Recent advances in biologic therapy of asthma and the role in therapy of chronic rhinosinusitis

F1000Research ◽

10.12688/f1000research.13170.1 ◽

2018 ◽

Vol 7 ◽

pp. 412 ◽

Cited By ~ 5

Author(s):

Rohit Divekar ◽

Devyani Lal

Keyword(s):

Immune Responses ◽

Chronic Rhinosinusitis ◽

Biologic Therapy ◽

Innate Immune ◽

Cytokine Receptors ◽

Nasal Airway ◽

Recent Developments ◽

Immune Pathways ◽

End Stage ◽

Made In

Great strides have been made in the last five years in understanding the pathology of chronic rhinosinusitis (CRS). CRS is now accepted to be the end-stage manifestation of inflammation resultant from various pathogenetic mechanisms. This has resulted in increasing recognition of distinct CRS endotypes. Such endotypes encompass a cluster of patients with similar pathogenic mechanisms that may have common therapeutic targets and responsiveness to interventions. The elucidation of mechanisms leading to the development of chronic upper (sino-nasal) airway inflammation has to some extent paralleled investigations of aberrant pathways operant in asthma. In this review, we focus on recent developments in understanding the innate immune pathways as well as adaptive (late) immune responses in CRS and asthma and their implication as potentially modifiable targets in CRS. Specific biologic therapy (that is, monoclonal antibodies targeting cytokines, cytokine receptors, or specific key molecules targeting inflammation) is an exciting proposition for the future of medical management of CRS. As of the writing of this article, the agents described are not approved for use in CRS; many have partial approval for use in asthma or are considered experimental.

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82. Blood Gene Expression Profiles in Neonates with Herpes Simplex Virus (HSV) Infection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.082 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S53-S53

Author(s):

Shira H Cohen ◽

Pablo J Sanchez ◽

Zhaohui Xu ◽

Rebecca M Glowinski ◽

Octavio Ramilo ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

T Cell ◽

Immune Responses ◽

Panel Member ◽

Differentially Expressed ◽

Research Support ◽

Disease Category ◽

Review Panel ◽

Immune Pathways

Abstract Background Neonatal HSV infection is associated with significant morbidity and mortality. Neonates with HSV infection can present with skin, eye, and mouth (SEM), central nervous system disease (CNS), and disseminated disease (DIS). We hypothesize that host immune responses may contribute to differences in disease presentation and outcomes. To address this knowledge gap, we analyzed host transcriptional immune profiles of neonates with HSV infection. Methods Infants < 6 weeks of age (24 (86%) < 4 weeks; 4 (14%) 4-6 weeks old) with neonatal HSV, and healthy infant controls (HC) were enrolled at Children’s Medical Center (Dallas, TX), and Nationwide Children’s Hospital (Columbus, OH) from 2007-2018. Whole blood samples were analyzed by RNA-seq. Modular analyses were performed to identify the immune pathways that were activated or suppressed according to each HSV disease category. Results Of the 28 infants with HSV infection, 9 had SEM (median [IQR] age: 14 [14-28] days), 10 CNS (age: 18 [15-29] days), and 9 DIS (age: 10 [7-10] days). Three infants with DIS died within 5 days of diagnosis. Statistical group comparisons between 13 HC and 18 infants with HSV disease (training set) identified 1,322 differentially expressed genes (neonatal HSV biosignature). This biosignature was validated in the remaining 10 infants with HSV disease (test set), and was characterized by significant overexpression of interferon (INF), inflammation, neutrophils, and monocyte genes and under-expression of T-cell genes. Further analysis according to HSV disease category confirmed overexpression of neutrophil and inflammation genes in infants with SEM, CNS and DIS (Fig 1). On the other hand, overexpression of INF and plasma cell genes, and further suppression of monocytes, cytotoxic/NK cells, and T-cell genes were only evident in children with DIS. Fig 1: Modular immune pathways according to HSV disease category Modules are groups of genes that shared a similar function. Each dot represents a transcriptional module with red indicating overexpression and blue underexpression in relation to healthy controls. The number and color intensity on the dot indicate the percentage of differentially expressed transcripts within a module. SEM: skin, eye mouth; CNS: central nervous system; DIS: disseminated HSV disease. Conclusion Transcriptional profiles of infants with HSV infection exhibited marked activation of the innate immune response irrespective of disease classification. Children with DIS showed more profound dysregulation and suppression of cellular immune responses. Transcriptional profiling may aid unravel mechanisms associated with clinical outcomes in neonatal HSV and inform future therapeutic and preventive strategies. Disclosures Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)

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Hemolymph protease-5 links the melanization and Toll immune pathways in the tobacco hornworm,Manduca sexta

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2004761117 ◽

2020 ◽

Vol 117 (38) ◽

pp. 23581-23587 ◽

Cited By ~ 1

Author(s):

Yang Wang ◽

Fan Yang ◽

Xiaolong Cao ◽

Zhen Zou ◽

Zhiqiang Lu ◽

...

Keyword(s):

Immune Responses ◽

Antimicrobial Peptides ◽

Serine Protease ◽

Manduca Sexta ◽

Serine Proteases ◽

Control Mechanisms ◽

Proteolytic Activation ◽

Cleavage Specificity ◽

Unique Site ◽

Immune Pathways

Proteolytic activation of phenoloxidase (PO) and the cytokine Spätzle during immune responses of insects is mediated by a network of hemolymph serine proteases (HPs) and noncatalytic serine protease homologs (SPHs) and inhibited by serpins. However, integration and conservation of the system and its control mechanisms are not fully understood. Here we present biochemical evidence that PO-catalyzed melanin formation, Spätzle-triggered Toll activation, and induced synthesis of antimicrobial peptides are stimulated via hemolymph (serine) protease 5 (HP5) inManduca sexta. Previous studies have demonstrated a protease cascade pathway in which HP14 activates proHP21; HP21 activates proPAP2 and proPAP3, which then activate proPO in the presence of a complex of SPH1 and SPH2. We found that both HP21 and PAP3 activate proHP5 by cleavage at ESDR176*IIGG. HP5 then cleaves proHP6 at a unique site of LDLH112*ILGG. HP6, an ortholog ofDrosophilaPersephone, activates both proHP8 and proPAP1. HP8 activates proSpätzle-1, whereas PAP1 cleaves and activates proPO. HP5 is inhibited byManduca sextaserpin-4, serpin-1A, and serpin-1J to regulate its activity. In summary, we have elucidated the physiological roles of HP5, a CLIPB with unique cleavage specificity (cutting after His) that coordinates immune responses in the caterpillar.

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The Potency of an Anti-MERS Coronavirus Subunit Vaccine Depends on a Unique Combinatorial Adjuvant Formulation

Vaccines ◽

10.3390/vaccines8020251 ◽

2020 ◽

Vol 8 (2) ◽

pp. 251 ◽

Cited By ~ 1

Author(s):

Parakkal Jovvian George ◽

Wanbo Tai ◽

Lanying Du ◽

Sara Lustigman

Keyword(s):

Immune Responses ◽

Antibody Response ◽

Protective Immunity ◽

Neutralizing Antibody ◽

Vaccine Antigen ◽

Receptor Binding Domain ◽

Subunit Vaccines ◽

Immune Pathways ◽

Draining Lymph Nodes ◽

Separate Injection

Vaccination is one of the most successful strategies to prevent human infectious diseases. Combinatorial adjuvants have gained increasing interest as they can stimulate multiple immune pathways and enhance the vaccine efficacy of subunit vaccines. We investigated the adjuvanticity of Aluminum (alum) in combination with rASP-1, a protein adjuvant, using the Middle East respiratory syndrome coronavirus MERS-CoV receptor-binding-domain (RBD) vaccine antigen. A highly enhanced anti-MERS-CoV neutralizing antibody response was induced when mice were immunized with rASP-1 and the alum-adjuvanted RBD vaccine in two separate injection sites as compared to mice immunized with RBD + rASP-1 + alum formulated into a single inoculum. The antibodies produced also significantly inhibited the binding of RBD to its cell-associated receptor. Moreover, immunization with rASP-1 co-administered with the alum-adjuvanted RBD vaccine in separate sites resulted in an enhanced frequency of TfH and GC B cells within the draining lymph nodes, both of which were positively associated with the titers of the neutralizing antibody response related to anti-MERS-CoV protective immunity. Our findings not only indicate that this unique combinatorial adjuvanted RBD vaccine regimen improved the immunogenicity of RBD, but also point to the importance of utilizing combinatorial adjuvants for the induction of synergistic protective immune responses.

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Modulation of IMD, Toll, and Jak/STAT Immune Pathways Genes in the Fat Body of Rhodnius prolixus During Trypanosoma rangeli Infection

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2020.598526 ◽

2021 ◽

Vol 10 ◽

Author(s):

Agustín Rolandelli ◽

Adeisa E. C. Nascimento ◽

Leticia S. Silva ◽

Rolando Rivera-Pomar ◽

Alessandra A. Guarneri

Keyword(s):

Transcription Factors ◽

Immune Responses ◽

Salivary Glands ◽

Fat Body ◽

Parasite Load ◽

Rhodnius Prolixus ◽

Trypanosoma Rangeli ◽

Infected Insect ◽

Immune Pathways

Trypanosoma rangeli is the second most common American trypanosome that infects man. It is vectored by triatomines from the genus Rhodnius, in which it invades the hemolymph and infects the salivary glands, avoiding the bug immune responses. In insects, these responses are initiated by well conserved pathways, mainly the IMD, Toll, and Jak/STAT. We hypothesize that long-term infection with T. rangeli in the gut or hemolymph of Rhodnius prolixus triggers different systemic immune responses, which influence the number of parasites that survive inside the vector. Thus, we investigated groups of insects with infections in the gut and/or hemolymph, and evaluated the parasite load and the expression in the fat body of transcription factors (Rp-Relish, Rp-Dorsal, and Rp-STAT) and inhibitors (Rp-Cactus and Rp-Caspar) of the IMD, Toll, and Jak/STAT pathways. We detected lower parasite counts in the gut of insects without hemolymph infection, compared to hemolymph-infected groups. Besides, we measured higher parasite numbers in the gut of bugs that were first inoculated with T. rangeli and then fed on infected mice, compared with control insects, indicating that hemolymph infection increases parasite numbers in the gut. Interestingly, we observed that genes from the three immune pathways where differentially modulated, depending on the region parasites were present, as we found (1) Rp-Relish downregulated in gut-and/or-hemolymph-infected insects, compared with controls; (2) Rp-Cactus upregulated in gut-infected insect, compared with controls and gut-and-hemolymph-infected groups; and (3) Rp-STAT downregulated in all groups of hemolymph-infected insects. Finally, we uncovered negative correlations between parasite loads in the gut and Rp-Relish and Rp-Cactus expression, and between parasite counts in the hemolymph and Rp-Relish levels, suggesting an association between parasite numbers and the IMD and Toll pathways. Overall, our findings reveal new players in R. prolixus–T. rangeli interactions that could be key for the capacity of the bug to transmit the pathogen.

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STING mediates immune responses in a unicellular choanoflagellate

10.1101/2021.05.13.443778 ◽

2021 ◽

Author(s):

Arielle Woznica ◽

Ashwani Kumar ◽

Carolyn R Sturge ◽

Chao Xing ◽

Nicole King ◽

...

Keyword(s):

Immune Responses ◽

Model System ◽

Innate Immune ◽

Dependent Manner ◽

First Line ◽

Immune Genes ◽

Cyclic Dinucleotides ◽

Immune Pathways ◽

Innate Immune Genes ◽

Cyclic Dinucleotide

Animals have evolved unique repertoires of innate immune genes and pathways that provide their first line of defense against pathogens. To reconstruct the ancestry of animal innate immunity, we have developed the choanoflagellate Monosiga brevicollis, one of the closest living relatives of animals, as a model for studying mechanisms underlying pathogen recognition and immune response. We found that M. brevicollis is killed by exposure to Pseudomonas aeruginosa bacteria and selectively avoids ingesting them. Moreover, M. brevicollis expresses STING, which, in animals, activates innate immune pathways in response to cyclic dinucleotides during pathogen sensing. M. brevicollis STING increases the susceptibility of M. brevicollis to P. aeruginosa-induced cell death and is required for responding to the cyclic dinucleotide 2'3' cGAMP. Furthermore, similar to animals, autophagic signaling in M. brevicollis is induced by 2'3' cGAMP in a STING-dependent manner. This study provides evidence for a pre-animal role for STING in antibacterial immunity and establishes M. brevicollis as a model system for the study of immune responses.

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