Host Protection Research Articles

Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?

Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?

Leishmania Vaccines: the Current Situation with Its Promising Aspect for the Future.

Leishmaniasis is a serious parasitic disease caused by Leishmania spp. transmitted through sandfly bites. This disease is a major public health concern worldwide. It can occur in 3 different clinical forms: cutaneous, mucocutaneous, and visceral Leishmaniasis (CL, MCL, and VL, respectively), caused by different Leishmania spp. Currently, licensed vaccines are unavailable for the treatment of human Leishmaniasis. The treatment and prevention of this disease rely mainly on chemotherapeutics, which are highly toxic and have an increasing resistance problem. The development of a safe, effective, and affordable vaccine for all forms of vector-borne disease is urgently needed to block transmission of the parasite between the host and vector. Immunological mechanisms in the pathogenesis of Leishmaniasis are complex. IL-12-driven Th1-type immune response plays a crucial role in host protection. The essential purpose of vaccination is to establish a protective immune response. To date, numerous vaccine studies have been conducted using live/attenuated/killed parasites, fractionated parasites, subunits, recombinant or DNA technology, delivery systems, and chimeric peptides. Most of these studies were limited to animals. In addition, standardization has not been achieved in these studies due to the differences in the virulence dynamics of the Leishmania spp. and the feasibility of the adjuvants. More studies are needed to develop a safe and effective vaccine, which is the most promising approach against Leishmania infection.

Pattern recognition receptor mediated innate immune response requires a Rif-dependent pathway

Small GTPases play critical roles in cell morphology, movement, and adhesion by dynamic regulation of actin cytoskeleton. The small Rho GTPase Rif/RhoF (Rho in filopodia) regulates the formation of filopodia and stress fibers in cells. Rif is highly expressed in a number of cell types in the immune system; however, it's role in immune system function is unclear. In this research, we found that Rif expression is necessary for NF-κB activation in primary immune cells, and mature dendritic cell (mature DCs) induced from Bone Marrow-Derived Dendritic Cells (BMDCs) isolated from Rif knock out (Rif KO) mice displayed impaired degradation of I-κBα, as well as reduced TNF-α secretion and p38 MAPK phosphorylation under LPS stimulation. Interestingly, we revealed that TLR agonists, such as LPS and poly (I:C), as well as bacterial virulence factor SopE could induce a transient increase in Rif activation in monocytes THP-1 cells. Furthermore, Rif was found to be an integral part of the TLR4, TLR3 and nodosome signaling complex. We further identified Src tyrosine kinases as upstream activator of Rif in both bacterial and viral induced immune responses. Moreover, activated Rif induces activation of transcription factors, such as NF-κB, AP-1 and IRF-3, and mediates inflammation through secretion of IL-6, IL-8 or TNFα. Rif activation by PRRs contributes in a variety of ways to protective host responses against invading microbes. Taken together, this study reveals that Rif is indispensable for both extracellular and intracellular pattern-recognition receptor-mediated innate immune responses. Rif possess broad anti-pathogenic effect and understanding of the molecular mechanisms by which this small Rho GTPase interferes with innate immune system will be beneficial to develop therapies against infectious agents.

Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever

Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis‐aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti‐microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1−/− mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1−/− mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1−/− mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1‐derived itaconate is a key factor in the macrophage‐mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.

Immunogenetics of posttraumatic stress disorder (PTSD) in women veterans

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric condition that is associated with concomitant immune system dysfunction. Here we evaluated the influence of genes involved in the human immune response, Human Leukocyte Antigen (HLA), on lifetime PTSD in primarily Caucasian women veterans. High-resolution HLA genotyping was completed for 372 participants. We assessed differences in HLA makeup between Control (n = 277) and lifetime PTSD (n = 95) groups. HLA was found to have a significant overall effect on lifetime PTSD occurrence (P < 0.00001). Of the 192 alleles identified in this sample, the frequencies of 15 alleles significantly differed between groups. Two alleles – HLA-A*02:01 and DPB1*04:01 –occurred more frequently in controls, presumably indicating protective effects. Thirteen alleles (6 Class I, 7 Class II) occurred more frequently in the lifetime PTSD group, presumably indicating susceptibility effects. In analysis evaluating the effect of the combined presence in individual participants of a protective allele and a susceptibility allele, the presence of a protective allele neutralized the effect of the susceptibility alleles. These findings, which add to the nascent literature on immunogenetics of PTSD, are discussed in terms of the evolutionary role of HLA in host protection against foreign antigens.

H3K36 methyltransferase NSD1 is essential for normal B1 and B2 cell development and germinal center formation.

B cells, which consist of two well-defined populations: B1 and B2 cells, which can produce antibodies that are essential for host protection against infections, through virus neutralization, opsonization and antibody-dependent cellular cytotoxicity. Epigenetic modifications, such as DNA methylation and histone modification could regulate immune cell differentiation and functions. In this study, we found a significant reduction of GC response in the B cell specific knockout of H3K36 methyltransferase NSD1 (Mb1-Cre+ NSD1fl/fl, NSD1B KO) mice compared with the wildtype control (Mb1-Cre+ NSD1+/+, NSD1B WT). We also demonstrated reduced production of high-affinity antibody, but increased production of low-affinity antibody in the NSD1B KO mice. Further analysis revealed that loss of NSD1 promoted the development of B1 cells by increasing the expression of Rap1b and Arid3a. In conclusion, our data suggest that NSD1 plays an important role in regulation the development of B1 and B2 cells, and the process of germinal center formation and high-affinity antibody production.

Mitochondria as disease-relevant organelles in rheumatoid arthritis.

Mitochondria are the controllers of cell metabolism and are recognized as decision makers in cell death pathways, organizers of cytoplasmic signaling networks, managers of cellular stress responses, and regulators of nuclear gene expression. Cells of the immune system are particularly dependent on mitochondrial resources, as they must swiftly respond to danger signals with activation, trafficking, migration, and generation of daughter cells. Analogously, faulty immune responses that lead to autoimmunity and tissue inflammation rely on mitochondria to supply energy, cell building blocks and metabolic intermediates. Emerging data endorse the concept that mitochondrial fitness, and the lack of it, is of particular relevance in the autoimmune disease rheumatoid arthritis (RA) where deviations of bioenergetic and biosynthetic flux affect T cells during early and late stages of disease. During early stages of RA, mitochondrial deficiency allows naïve RA T cells to lose self-tolerance, biasing fundamental choices of the immune system toward immune-mediated tissue damage and away from host protection. During late stages of RA, mitochondrial abnormalities shape the response patterns of RA effector T cells engaged in the inflammatory lesions, enabling chronicity of tissue damage and tissue remodeling. In the inflamed joint, autoreactive T cells partner with metabolically reprogrammed tissue macrophages that specialize in antigen-presentation and survive by adapting to the glucose-deplete tissue microenvironment. Here, we summarize recent data on dysfunctional mitochondria and mitochondria-derived signals relevant in the RA disease process that offer novel opportunities to deter autoimmune tissue inflammation by metabolic interference.

Host Protective Immunity against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) and the COVID-19 Vaccine-Induced Immunity against SARS-CoV-2 and Its Variants.

The world is now apparently at the last/recovery stage of the COVID-19 pandemic, starting from 29 December 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the progression of time, several mutations have taken place in the original SARS-CoV-2 Wuhan strain, which have generated variants of concern (VOC). Therefore, combatting COVID-19 has required the development of COVID-19 vaccines using several platforms. The immunity induced by those vaccines is vital to study in order to assure total protection against SARS-CoV-2 and its emerging variants. Indeed, understanding and identifying COVID-19 protection mechanisms or the host immune responses are of significance in terms of designing both new and repurposed drugs as well as the development of novel vaccines with few to no side effects. Detecting the immune mechanisms for host protection against SARS-CoV-2 and its variants is crucial for the development of novel COVID-19 vaccines as well as to monitor the effectiveness of the currently used vaccines worldwide. Immune memory in terms of the production of neutralizing antibodies (NAbs) during reinfection is also very crucial to formulate the vaccine administration schedule/vaccine doses. The response of antigen-specific antibodies and NAbs as well as T cell responses, along with the protective cytokine production and the innate immunity generated upon COVID-19 vaccination, are discussed in the current review in comparison to the features of naturally induced protective immunity.

Appraisal of Saliva and Its Sensory Perception in Reproductive Transitions of Women: A Review.

There are physical, hormonal, and psychological variations in women, which affect their health in general. This may influence the environment of oral cavity, specific to salivary stream rate, salivary pH, and buffering capacity. Saliva is a perplexing liquid containing an assortment of mucosal host protection factors from diverse salivary organs and crevicular liquid. Though saliva has been inspected with regard to several physiological and pathological conditions, the association of various properties of saliva with different phases of women's menstrual cycle remains unexplored. Because diet and salivary stream rate are correlated, food not only affects salivary flow but also has an impact on sensory perception. One of the most vital human senses, taste, is crucial in determining a person's dietary requirements, which in turn influences eating habits and, eventually, human nourishment. As a result, along with variations in salivary stream rate and pH, the capability to sense taste may also alter during the phases of pregnancy, menstruation, and menopause. Hence, this review article is designed to assess salivary stream rate, pH, and gustatory function in several phases of women's lives to determine the impact of menstruation, pregnancy, and menopause on saliva as well as the reciprocal relationship between saliva and gustatory function.

Genetic resilience in chickens against bacterial, viral and protozoal pathogens.

The genome contributes to the uniqueness of an individual breed, and enables distinctive characteristics to be passed from one generation to the next. The allelic heterogeneity of a certain breed results in a different response to a pathogen with different genomic expression. Disease resistance in chicken is a polygenic trait that involves different genes that confer resistance against pathogens. Such resistance also involves major histocompatibility (MHC) molecules, immunoglobulins, cytokines, interleukins, T and B cells, and CD4+ and CD8+ T lymphocytes, which are involved in host protection. The MHC is associated with antigen presentation, antibody production, and cytokine stimulation, which highlight its role in disease resistance. The natural resistance-associated macrophage protein 1 (Nramp-1), interferon (IFN), myxovirus-resistance gene, myeloid differentiation primary response 88 (MyD88), receptor-interacting serine/threonine kinase 2 (RIP2), and heterophile cells are involved in disease resistance and susceptibility of chicken. Studies related to disease resistance genetics, epigenetics, and quantitative trait loci would enable the identification of resistance markers and the development of disease resistance breeds. Microbial infections are responsible for significant outbreaks and have blighted the poultry industry. Breeding disease-resistant chicken strains may be helpful in tackling pathogens and increasing the current understanding on host genetics in the fight against communicable diseases. Advanced technologies, such as the CRISPR/Cas9 system, whole genome sequencing, RNA sequencing, and high-density single nucleotide polymorphism (SNP) genotyping, aid the development of resistant breeds, which would significantly decrease the use of antibiotics and vaccination in poultry. In this review, we aimed to reveal the recent genetic basis of infection and genomic modification that increase resistance against different pathogens in chickens.

T cell aging as a risk factor for autoimmunity

Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur during the second half of life, counterintuitive to the concept of excess adaptive immunity driving immune-mediated tissue damage. T cells are particularly susceptible to aging-imposed changes, as they are under extreme proliferative pressure to fulfill the demands of clonal expansion and of homeostatic T cell repopulation. T cells in older adults have a footprint of genetic and epigenetic changes, lack mitochondrial fitness, and fail to maintain proteostasis, diverging them from host protection to host injury. Here, we review recent progress in understanding how the human T-cell system ages and the evidence detailing how T cell aging contributes to autoimmune conditions. T cell aging is now recognized as a risk determinant in two prototypic autoimmune syndromes; rheumatoid arthritis and giant cell arteritis. The emerging concept adds susceptibility to autoimmune and autoinflammatory disease to the spectrum of aging-imposed adaptations and opens new opportunities for immunomodulatory therapy by restoring the functional intactness of aging T cells.

The echinoid complement system inferred from genome sequence searches

The vertebrate complement cascade is an essential host protection system that functions at the intersection of adaptive and innate immunity. However, it was originally assumed that complement was present only in vertebrates because it was activated by antibodies and functioned with adaptive immunity. Subsequently, the identification of the key component, SpC3, in sea urchins plus a wide range of other invertebrates significantly expanded the concepts of how complement functions. Because there are few reports on the echinoid complement system, an alternative approach to identify complement components in echinoderms is to search the deduced proteins encoded in the genomes. This approach identified known and putative members of the lectin and alternative activation pathways, but members of the terminal pathway are absent. Several types of complement receptors are encoded in the genomes. Complement regulatory proteins composed of complement control protein (CCP) modules are identified that may control the activation pathways and the convertases. Other regulatory proteins without CCP modules are also identified, however regulators of the terminal pathway are absent. The expansion of genes encoding proteins with Macpf domains is noteworthy because this domain is a signature of perforin and proteins in the terminal pathway. The results suggest that the major functions of the echinoid complement system are detection of foreign targets by the proteins that initiate the activation pathways resulting in opsonization by SpC3b fragments to augment phagocytosis and destruction of the foreign targets by the immune cells.

Antibacterial and Anti-Inflammatory Potential of Chinese Medicinal Herbs: Lonicerae flos, Lonicerae japonicae flos, Scutellaria baicalensis Georgi, and Forsythia suspensa

Chinese herbal medicine (CHM) represents a potent, safe, and efficacious reservoir of treatment options against an array of microbial infections and inflammatory diseases. It has a long history of positive clinical outcomes with minimal or no side effects while enhancing and bolstering the host's protection against infections. With its unique ability to prevent, treat, and manage a wide range of diseased conditions, CHM has been successfully practiced in China for thousands of years. In the modern medical era, where harsh therapeutic drugs and antimicrobial resistance (AMR) present a significant challenge, CHM warrants further exploration. The present review highlights and focuses on 4 major CHM-based herbs, that is, ( Lonicerae flos [ LF] , Lonicerae japonicae flos [ LJF] , Scutellaria baicalensis Georgi [ SBG] , and Forsythia suspensa [ FS]) in terms of their antibacterial and anti-inflammatory efficacies. A detailed literature survey was done by the team using a systematic electronic search from PubMed, Science Direct, Google Scholar, Research Gate, books, etc. This was followed by data collecting, pertinent data extraction, in-depth analysis, and composing the final review. Each herb has been discussed in detail describing its mechanism adopted and the bioactive components involved in alleviating bacterial infections and inflammatory damage. Further, proof of efficacy by detailing the major past studies and major findings has been discussed for each of the 4 herbs. This review will give the scientific community the opportunity to update their knowledge on the subject, which is crucial for heralding the process of bringing CHM-based medicines closer to clinical development given the area of alternative medicine's rapid advancements.

Candida lipase packs a punch against IL-17

In this issue of Cell Host &amp; Microbe, Basso etal. delineate a mechanism for the fungal lipase Lip2 during systemic infection with Candida albicans, the most common human fungal pathogen. They find that lipids liberated by Lip2 can manipulate the protective host cytokine response, thereby enhancing fungal virulence.

The Role of Interleukin-17 in Tissue Protection during Radiation-Induced Oral Mucositis

<h3>Purpose/Objective(s)</h3> Oral mucositis (OM) is a common non-hematological side effect of radiotherapy and chemotherapy for head and neck cancers. Tissue injury associated with OM is painful, and can be difficult to treat. While the clinical progression of OM is understood, the signaling networks involved in the progression and resolution of damage have not been fully elucidated. Interleukin-17 (IL-17) is a proinflammatory cytokine produced by ‘type-17' lymphocytes, including T-helper 17 (Th17) cells. IL-17 is important in host protection against microbes, but it also can be pathogenic in autoimmune conditions. The role of IL-17 in other inflammatory disorders is not straightforward either. Due to the proliferative and inflammatory properties of IL-17 it is implicated in several malignancies, including esophageal cancer and tongue squamous cell carcinoma. Yet, in the distal gastrointestinal tract, IL-17 can be protective in tissue repair and maintenance. We set out to determine the role of IL-17 during severe ulceration of the oral mucosa associated with head and neck irradiation. We hypothesized that IL-17 is beneficial in repair of the oral mucosa after radiation exposure. <h3>Materials/Methods</h3> We approached this question by exposing wild-type (WT) mice and mice deficient in the receptor for IL-17, IL-17RA (<i>Il17ra</i>^−/−), to head and neck irradiation (HNI)-induced OM. Mice received a single dose of 22.5Gy of targeted irradiation using 6 MeV electrons from a linear accelerator. Tongue tissue was excised and processed for RNA-Seq analysis. The tissue was assessed macroscopically and histologically for damage, and the immune cells present in the oral tissue after HNI were determined by flow cytometry. <h3>Results</h3> RNA-Seq of oral tissue showed elevated expression of IL-17 and related immune pathways in response to HNI. Mice lacking IL-17RA exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in the <i>Il17ra</i>^−/- mice and components associated with healing were diminished. The absence of IL-17RA also resulted in excess neutrophils and immunopathology compared to WT mice. <h3>Conclusion</h3> IL-17RA is required to prevent severe mucosal damage, and optimize healing after ionizing radiation. IL-17RA contributes to the proliferative capacity of the oral epithelia and maintains immune cell balance in the oral mucosa creating an environment conducive to restoration of the damaged tissue. This important contribution of IL-17 post-irradiation has implications for other cancer therapies related to the Th17 pathway.

Enhanced Influenza Immunity by Nasal Mucosal Administration of the TPGS-Modified Liposomal Vaccine.

Influenza infection is difficult to prevent, control, and treat because of rapid viral mutation, fast disease progression, and high mortality. Vaccination is the main means by which to prevent and control influenza, but effectiveness is limited in that poor cellular uptake and weak immunogenicity of vaccines provides less than optimal host protection. Liposomal influenza vaccines are a promising strategy to overcome these limitations and the use of liposomal immune modulators and intranasal administration of liposomal influenza vaccines may be a means by which to improve influenza protection. The cationic lipids, i.e., dimethyldioctadecylammonium (DDA), 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (DSPC), and D-α-tocopherol polyethylene glycol 1000 (TPGS) can form blank liposomes, which can incorporate influenza antigens to produce an influenza vaccine (DDA-DSPC-TPGS). Herein, this vaccine was shown to induce dendritic cell maturation, increase host cellular uptake of the vaccine, and enhance immune responses both in vitro and in vivo. The addition of TPGS, as an amphiphilic immune adjuvant, significantly reduced the toxicity of the DDA liposomal influenza vaccine. Further, the polyethylene glycol component and tocopherol structure of TPGS enhanced the cellular uptake of the vaccine by means of stealth properties and the capacity to inhibit cellular efflux. After nasal mucosal immunization, enhanced cellular uptake rates and abundant immune cells in the nasopharyngeal-associated lymphoid tissue promoted the production of immunoglobulin A, immunoglobulin G1, and interferon-γ, which in turn mediated a more robust immune response against influenza virus. In summary, the DDA-DSPC-TPGS influenza vaccine is a safe and effective means by which to activate the immune system. The results herein provide an effective strategy by which to overcome current difficulties associated with the prevention and treatment of influenza.

Communication is key: Innate immune cells regulate host protection to helminths.

Parasitic helminth infections remain a significant global health issue and are responsible for devastating morbidity and economic hardships. During infection, helminths migrate through different host organs, which results in substantial tissue damage and the release of diverse effector molecules by both hematopoietic and non-hematopoietic cells. Thus, host protective responses to helminths must initiate mechanisms that help to promote worm clearance while simultaneously mitigating tissue injury. The specialized immunity that promotes these responses is termed type 2 inflammation and is initiated by the recruitment and activation of hematopoietic stem/progenitor cells, mast cells, basophils, eosinophils, dendritic cells, neutrophils, macrophages, myeloid-derived suppressor cells, and group 2 innate lymphoid cells. Recent work has also revealed the importance of neuron-derived signals in regulating type 2 inflammation and antihelminth immunity. These studies suggest that multiple body systems coordinate to promote optimal outcomes post-infection. In this review, we will describe the innate immune events that direct the scope and intensity of antihelminth immunity. Further, we will highlight the recent progress made in our understanding of the neuro-immune interactions that regulate these pathways and discuss the conceptual advances they promote.

137 Standing in the gap of Neonatal Microbe-Host Barrier Function

Abstract The provision of mammary secretions in the form of colostrum and mature milk for newborns is an essential survival function that has evolved over millennia in mammalian species. Colostrum serves a vital function for neonates by providing nutrients for energy and growth as they transition from placental nutrition to oral ingestion of more complex macromolecules, including lactose, proteins, and triglycerides. Colostrum also provides critical immune protection from colonizing commensal and pathogenic microbes that supports neonatal immunity until maturation of the immune system. This concept of homologous passive immunity conferred by colostrum is well known in farm animal species and has been largely attributed to immunoglobulins transferred from mother to offspring. Heterologous passive immunity is also an approach whereby bovine colostrum obtained from normal or hyperimmunized cows is used therapeutically to prevent specific GI diseases in swine and human infants. The critical importance of colostrum to survival of newborn farm animals also holds true in the prevention of intestinal diseases, such as necrotizing enterocolitis (NEC), in hospitalized premature infants. In preterm infants, mother’s own milk may not always be available and infants are instead fed donor human milk, which provides effective protection against NEC. Whether the benefits of human milk in the prevention of NEC are due to immunoglobulins is not well established. These scenarios whereby colostrum from different species or different mothers within a species protect the neonatal gut point to common elements of host protection. New experimental approaches and tools are being applied to understanding the molecular mechanism of how components of maternal milk impact gut microbial colonization and interaction with the host immune system.

Classical and γδ T cells are each independently sufficient to establish protection against a classical strain of Klebsiella pneumoniae.

Infections with classical strains of the Gram-negative bacterium Klebsiella pneumoniae pose a significant clinical challenge due to rising antibiotic resistance. We previously established a lung inoculation plus challenge model using live, classical K. pneumoniae in order to study host protection. Here, we employ this model to dissect adaptive immune responses to this critical pathogen. First, we performed convalescent serum transfers from inoculated mice to naïve recipients and found that classical K. pneumoniae infection outcomes, unlike hypervirulent K. pneumoniae infection outcomes, were not improved. This suggests that circulating antibody responses alone are not sufficient to mediate protection against this classical strain. Hence, we evaluated the role of T cells in protection against classical K. pneumoniae reinfection and demonstrated that mice lacking T cells are unable to establish a protective response. However, mice individually deficient in either of the major T cell subsets, γδ or αβ (classical T cells), effectively mount a protective response, indicating either subset alone is sufficient to mediate protection. Sequestration of T cells in secondary lymphoid organs during the challenge infection did not ablate protection, indicating the circulating T cell pool is not required for the protective phenotype. Finally, we demonstrate that depletion of T cells during initial infection eliminates protection against challenge. Collectively, these experiments demonstrate the imperative contribution of T cells to protective immunity against classical K. pneumoniae and will guide further inquiries into host effector responses required to control this infection.

Comparison of H7N9 and H9N2 influenza infections in mouse model unravels the importance of early innate immune response in host protection.

The outcome of infection with influenza A virus is determined by a complex virus-host interaction. A new H7N9 virus of avian origin crossed the species barrier to infect humans, causing high mortality and emerged as a potential pandemic threat. The mechanisms underlying the virulence and pathogenicity of H7N9 virus remains elusive. H7N9 virus originated from a genetic assortment that involved the avian H9N2 virus, which was the donor of the six internal genes. Unlike the H7N9 virus, the H9N2 virus caused only mild phenotype in infected mice. In this study, we used the mouse infection model to dissect the difference in the host response between the H7N9 and H9N2 viruses. Through analyzing transcriptomics of infected lungs, we surprisingly found that the H9N2 infection elicited an earlier induction of innate immunity than H7N9 infection. This finding was further corroborated by an immunohistochemical study demonstrating earlier recruitment of macrophage to the H9N2-infected lung than the H7N9-infected lung, which could occur as early as 6 hours post infection. In contrast, H7N9 infection was characterized by a late, strong lung CD8+ T cell response that is more robust than H9N2 infection. The different pattern of immune response may underlie more severe lung pathology caused by H7N9 infection compared to H9N2 infection. Finally, we could show that co-infection of the H9N2 virus protected mice from the challenge of both H7N9 and PR8 viruses, thereby strengthening the importance of the induction of an early innate immunity in the host’s defense against influenza infection. Collectively, our study unraveled a previously unidentified difference in host response between H7N9 and H9N2 infection and shed new insight on how virus-host interaction shapes the in vivo outcome of influenza infection.