The innate immune response to lower respiratory tract E. Coli infection and the role of the CCL2-CCR2 axis in neonatal mice

ABSTRACTThe nasal-mucosa constitutes the primary entry site for respiratory viruses including SARS-CoV-2. While the imbalanced innate immune response of end-stage COVID-19 has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local-mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with rapid increase in tissue-associated viral sub-genomic mRNA, and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon stimulated genes, cytokines and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tract, that are distinct to SARS-CoV-2. The studies shed light on the role of the nasal-mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19.IMPORTANCEIn order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal-mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues, infected in parallel with SARS-CoV-2 and influenza virus, we have revealed distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal-mucosal infection model can be employed to assess the impact of viral evolutionary changes, and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

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Human nasal and lung tissues infected ex vivo with SARS-CoV-2 provide insights into differential tissue-specific and virus-specific innate immune responses in the upper and lower respiratory tract

Journal of Virology ◽

10.1128/jvi.00130-21 ◽

2021 ◽

Author(s):

Or Alfi ◽

Arkadi Yakirevitch ◽

Ori Wald ◽

Ori Wandel ◽

Uzi Izhar ◽

...

Keyword(s):

Immune Response ◽

Influenza Virus ◽

Immune Responses ◽

Respiratory Tract ◽

Nasal Mucosa ◽

Innate Immune Response ◽

Lower Respiratory Tract ◽

Influenza Virus Infection ◽

Innate Immune ◽

Innate Immune Responses

The nasal-mucosa constitutes the primary entry site for respiratory viruses including SARS-CoV-2. While the imbalanced innate immune response of end-stage COVID-19 has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local-mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with rapid increase in tissue-associated viral sub-genomic mRNA, and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon stimulated genes, cytokines and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tract, that are distinct to SARS-CoV-2. The studies shed light on the role of the nasal-mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal-mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues, infected in parallel with SARS-CoV-2 and influenza virus, we have revealed distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal-mucosal infection model can be employed to assess the impact of viral evolutionary changes, and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

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MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract

Journal of Infection and Public Health ◽

10.1016/j.jiph.2020.01.179 ◽

2020 ◽

Vol 13 (2) ◽

pp. 371-372

Author(s):

B. Alosaimi ◽

M. Awadalla ◽

M. Enani

Keyword(s):

Immune Response ◽

Respiratory Tract ◽

Innate Immune Response ◽

Lower Respiratory Tract ◽

Innate Immune ◽

Th2 Cytokines ◽

Genes Encoding ◽

Th1 And Th2 Cytokines ◽

Th1 And Th2

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Role of Caspase 1 in Murine Antibacterial Host Defenses and Lethal Endotoxemia

Infection and Immunity ◽

10.1128/iai.70.12.6896-6903.2002 ◽

2002 ◽

Vol 70 (12) ◽

pp. 6896-6903 ◽

Cited By ~ 46

Author(s):

Vishwas D. Joshi ◽

Dhananjaya V. Kalvakolanu ◽

John R. Hebel ◽

Jeffrey D. Hasday ◽

Alan S. Cross

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Endotoxic Shock ◽

Innate Immune ◽

Mrna Levels ◽

Host Defenses ◽

E Coli ◽

Caspase 1 ◽

Reverse Transcription Pcr

ABSTRACT Sepsis is thought to result from an exaggerated innate immune response to microbial components such as lipopolysaccharide (LPS), but the involvement of a specific mechanism(s) has not been identified. We studied the role of caspase 1 (Cas-1) in the murine innate immune response to infection with gram-negative bacteria and to nonlethal and lethal doses of LPS. cas-1 −/− and Cas-1 inhibitor (Ac-YVAD-CHO)-treated cas-1 +/+ mice were two- to threefold more susceptible to lethal Escherichia coli infection than cas-1 +/+ mice. Administration of Cas-1 products, interleukin-18 (IL-18) or IL-1β, protected three of three and six of seven mice, respectively, from lethal infection with E. coli compared to none of six of untreated mice (P = 0.0082). Therefore, cas-1 is essential for antibacterial host defense. Nonlethal (75 μg) and lethal (500 μg) doses of LPS induce different patterns of gamma interferon, IL-1β, and IL-18 expression. Consequently, the role of Cas-1, which cleaves pro-IL-18 and pro-IL-1β to their active forms, was investigated in these disparate conditions by using enzymatic assay and reverse transcription-PCR. At 75 μg, LPS induced a transient increase in IL-1β and IL-18 levels in serum, whereas at 500 μg it induced a 1.5-fold-higher IL-18 level in serum, which increased till death. At 75 μg of LPS, splenic cas-1 mRNA expression remained unchanged at all time points, but activity increased transiently at 3 h. In lethally treated mice, Cas-1 activity remained elevated until death; however, cas-1 mRNA levels increased at 3 h and decreased to basal levels by 8 h. Treatment with Cas-1 inhibitor protected mice from lethal endotoxemia. Thus, Cas-1 is essential for innate antibacterial host defenses and may represent a mechanism of innate immunity that upon excessive stimulation by microbial components may lead to endotoxic shock.

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