The innate immune system is a collective network of cell types involved in cell recruitment and activation using a robust and refined communication system. Engagement of receptor-mediated intracellular signaling initiates communication cascades by conveying information about the host cell status to surrounding cells for surveillance and protection. Comprehensive profiling of innate immune cells is challenging due to low cell numbers, high dynamic range of the cellular proteome, low abundance of secreted proteins, and the release of degradative enzymes (e.g., proteases).However, recent advances in mass spectrometry-based proteomics provides the capability to overcome these limitations through profiling the dynamics of cellular processes, signaling cascades, post-translational modifications, and interaction networks. Moreover, integration of technologies and molecular datasets provide a holistic view of a complex and intricate network of communications underscoring host defense and tissue homeostasis mechanisms. In this Review, we explore the diverse applications of mass spectrometry-based proteomics in innate immunity to define communication patterns of the innate immune cells during health and disease. We also provide a technical overview of mass spectrometry-based proteomic workflows, with a focus on bottom-up approaches, and we present the emerging role of proteomics in immune-based drug discovery while providing a perspective on new applications in the future.

Antibody-dependent enhancement (ADE) is an atypical immunological paradox commonly associated with dengue virus re-infection. However, various research models have demonstrated this phenomenon with other viral families, including Coronaviridae. Recently, ADE in SARS-CoV-2 has emerged as one hypothesis to explain severe clinical manifestations. Whether SARS-CoV-2 is augmented by ADE remains undetermined and has therefore garnered criticism for the improper attribution of the phenomenon to the pandemic. Thus, critical evaluation of ADE in SARS-CoV-2 vaccine development will be indispensable to avoid a global setback and the erosion of public trust.

As Brazil was preparing to host the 2016 Summer Olympic Games, they were also experiencing a Zika virus (ZIKV) epidemic coinciding with rising cases of microcephaly, a congenital disorder that causes severe lifelong neurological impairment. ZIKV was later confirmed as the first sexually transmitted teratogenic Flavivirus. During the epidemic, ZIKV cases were being diagnosed as mild forms of Dengue virus (DENV), another mosquito‐borne Flavivirus known for causing Dengue hemorrhagic fever (DHF). DHF is augmented by a process called antibody‐dependent enhancement (ADE), in which pre‐existing DENV immunity can render an individual more susceptible to a subsequent DENV exposure. Based on structural similarities between ZIKV and DENV surface proteins, emerging evidence suggests anti‐DENV antibodies can cross‐react with ZIKV at non‐neutralizing levels characteristic of ADE. Therefore, a pre‐existing DENV immunity may enhance ZIKV infection and could explain the severe ZIKV manifestations in Brazil. Sentinel cells positioned in the periphery that detect infection are integral in coordinating early immune defenses. Among these immune cells, the mast cell (MC) is uniquely positioned in the intradermal space, the first point of contact between the host and an infected mosquito. MC responses to virus can be modelled in vitro, including via use of the well‐characterized KU812 cell line which express surface proteins that may be exploited by ZIKV and DENV. In particular, Fcγ receptors (FcγR), which can bind to anti‐DENV IgG antibodies that cross‐react with ZIKV can facilitate ADE. However, to our knowledge this mechanism has never been explored in the context of ZIKV‐MC interactions. Here, we sought to determine if the FcγR‐bearing KU812 MC is susceptible to (1) direct ZIKV infection and (2) ZIKV infection in the presence of anti‐DENV antibodies that cross‐react with ZIKV. Cells were infected with PRVABC59‐ZIKV (MOI=1) directly or in the presence of anti‐DENV antibodies for 72 hours. Supernatants of ZIKV infected MC cultures were then harvested and virus titre quantified by plaque assay. A significant increase in viral titre (104 PFU/mL) was detected in MCs directly infected with ZIKV compared to MCs infected with UV‐inactivated ZIKV (0 PFU/mL). Furthermore, a significant viral titre (106 PFU/mL) was detected in MCs infected with ZIKV pre‐incubated with anti‐DENV antibodies when compared to MCs infected with ZIKV pre‐incubated with isotype control antibodies (104 PFU/mL). Additionally, significant CCL5 secretion was detected by ELISA in MCs infected in the presence of DENV antibodies compared to MCs directly infected with ZIKV, suggesting a distinct chemokine response to infection in each context. This work is the first to define ZIKV infection in a mast cell model. Additionally, we report an antigen‐specific antibody‐mediated infection of ZIKV in KU812 MCs. Therefore, MCs may be a contributor in ZIKV pathogenesis during a primary exposure and significantly augment ZIKV infection in the context of pre‐existing DENV immunity. S...

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Antibodies generated against one dengue serotype can enhance infection of another by a phenomenon called antibody-dependent enhancement (ADE). Additionally, antigenic similarities between Zika and dengue viruses can promote Zika virus infection by way of ADE in vitro using these very same anti-dengue antibodies.