Cry1Ac protoxin from Bacillus thuringiensis promotes macrophage activation by upregulating CD80 and CD86 and by inducing IL-6, MCP-1 and TNF-α cytokines

Moreno‐Fierros, Leticia; García‐Hernández, Ana Lilia; Ilhuicatzi-Alvarado, Damaris; Rivera-Santiago, Lucio; Torres‐Martínez, Marilu; Rubio-Infante, Néstor; Legorreta-Herrera, Martha

doi:10.1016/j.intimp.2013.10.005

Cited by 41 publications

(37 citation statements)

References 46 publications

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“…However, interestingly, the authors noted that Cry1Ab caused a four-fold increase in the conductance of potassium (Stumpff et al, 2007). Also, as mentioned later, our group has demonstrated that the protoxin Cry1Ac can induce murine macrophage activation both in vitro and in vivo (Moreno-Fierros et al, 2013). Also, as mentioned later, our group has demonstrated that the protoxin Cry1Ac can induce murine macrophage activation both in vitro and in vivo (Moreno-Fierros et al, 2013).…”

Section: In Vivo and In Vitro Toxicological Studies With Cry Purifiedsupporting

confidence: 58%

“…For example, Cry1Ab in MON810 maize was estimated to be 0.0013% of the protein content (Adel-Patient et al, 2011). However, if we consider that an estimated dose of Cry1Ac of approximately 0.3-2 mg kg -1 is needed to achieve a biological effect (for example, an immunostimulating effect with Cry1Ac via the intranasal route in mice can be elicited with doses of 5-50 μg per 25-g mice (Guerrero et al, 2004;Moreno-Fierros et al, 2013). Given that a 60-kg person would have to eat 18 461 kg day -1 corn to achieve the highest fed dose tested in mice (4 g kg -1 ), which is considered non-lethal (Table 3).…”

Section: Box 2 Criteria To Define Toxicitymentioning

confidence: 99%

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An overview of the safety and biological effects of Bacillus thuringiensis Cry toxins in mammals

Rubio-Infante

Moreno‐Fierros

2015

J of Applied Toxicology

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Crystal proteins (Cry) produced during the growth and sporulation phases of Bacillus thuringiensis (Bt) bacterium are known as delta endotoxins. These toxins are being used worldwide as bioinsecticides to control pests in agriculture, and some Cry toxins are used against mosquitoes to control vector transmission. This review summarizes the relevant information currently available regarding the biosafety and biological effects that Bt and its insecticidal Cry proteins elicit in mammals. This work was performed because of concerns regarding the possible health impact of Cry toxins on vertebrates, particularly because Bt toxins might be associated with immune-activating or allergic responses. The controversial data published to date are discussed in this review considering earlier toxicological studies of B. thuringiensis, spores, toxins and Bt crops. We discussed the experimental studies performed in humans, mice, rats and sheep as well as in diverse mammalian cell lines. Although the term 'toxic' is not appropriate for defining the effects these toxins have on mammals, they cannot be considered innocuous, as they have some physiological effects that may become pathological; thus, trials that are more comprehensive are necessary to determine their effects on mammals because knowledge in this field remains limited.

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Section: In Vivo and In Vitro Toxicological Studies With Cry Purifiedsupporting

confidence: 58%

Section: Box 2 Criteria To Define Toxicitymentioning

confidence: 99%

An overview of the safety and biological effects of Bacillus thuringiensis Cry toxins in mammals

Rubio-Infante

Moreno‐Fierros

2015

J of Applied Toxicology

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“…In one study, Cry1Ac was investigated for in vivo activation of a variety of macrophages after intraperitoneal or intranasal administration in BALB/c mice. The protoxin upregulated costimulatory molecules on macrophages and enhanced the production of the TNF-α, IL-6, and MCP-1 [26]. In another study, Cry1Ac delivered intranasally generated an antibody response, stimulated nasal-associated lymphoid tissue lymphocytes to produce Th2 cytokines, and induced a proportion of T cells to spontaneously produce IL-4, IL-5, and IL-10 [27].…”

Section: Discussionmentioning

confidence: 96%

“…Some investigators suggest that Bt -maize may have an adjuvant effect that requires testing [17]–[20], [26]–[30]. In 2009, EFSA reported that consumption of Bt -maize by humans and animals is safe [14].…”

Section: Discussionmentioning

confidence: 99%

No Adjuvant Effect of Bacillus thuringiensis-Maize on Allergic Responses in Mice

et al. 2014

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Genetically modified (GM) foods are evaluated carefully for their ability to induce allergic disease. However, few studies have tested the capacity of a GM food to act as an adjuvant, i.e. influencing allergic responses to other unrelated allergens at acute onset and in individuals with pre-existing allergy. We sought to evaluate the effect of short-term feeding of GM Bacillus thuringiensis (Bt)-maize (MON810) on the initiation and relapse of allergic asthma in mice. BALB/c mice were provided a diet containing 33% GM or non-GM maize for up to 34 days either before ovalbumin (OVA)-induced experimental allergic asthma or disease relapse in mice with pre-existing allergy. We observed that GM-maize feeding did not affect OVA-induced eosinophilic airway and lung inflammation, mucus hypersecretion or OVA-specific antibody production at initiation or relapse of allergic asthma. There was no adjuvant effect upon GM-maize consumption on the onset or severity of allergic responses in a mouse model of allergic asthma.

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“…Stronger adjuvant effects have been shown with recombinant soluble Cry1Ac protoxin administered to mice by the intraperitoneal (IP) or the intragastric (IG) route of exposure 237 . The mechanism of action through which the Cry1Ac protein exerts its immunomodulatory effects on antigen presenting cells, such as macrophages, is unknown; two studies from Moreno-Fierros et al showed that Cry1Ac activates macrophages by inducing the upregulation of CD86, CD80 MHCII and the production of IL-6, TNF-α and MCP-1, and these effects are mediated by MAPK pathways and the transcription factor NF-kB 202,244 . The mechanism of action through which the Cry1Ac protein exerts its immunomodulatory effects on antigen presenting cells, such as macrophages, is unknown; two studies from Moreno-Fierros et al showed that Cry1Ac activates macrophages by inducing the upregulation of CD86, CD80 MHCII and the production of IL-6, TNF-α and MCP-1, and these effects are mediated by MAPK pathways and the transcription factor NF-kB 202,244 .…”

Section: Adjuvanticity and Immunogenicity Of Cry Proteinsmentioning

confidence: 99%

Literature review in support of adjuvanticity/immunogenicity assessment of proteins

Parenti

Santoro

Río

et al. 2019

EFS3

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Based on the risk assessment of genetically modified plants, according to Implementing Regulation (EU) No 503/201321 "In cases when known functional aspects of the newly expressed protein or structural similarity to known strong adjuvants may indicate possible adjuvant activity, the applicant shall assess the possible role of these proteins as adjuvants". To further investigate the topic, an EFSA procurement was launched requesting a comprehensive literature review and critically appraisal on adjuvanticity and immunogenicity of proteins. A systematic literature search and critical review was performed, identifying 299 relevant publications. From the evaluation of the relevant literature emerged that: i) a clear classification of adjuvant and immunogens of proteins cannot be done; ii) structural features able to modulate adjuvanticity and immunogenicity are mainly ascribed to therapeutic proteins and in the context of allergenicity and cross-reactivity; iii) factors affecting the propensity of a protein to stimulate immune response are aggregation, thermal processing, digestion, food matrix, among others; iv) different proteins are described to have immunomodulatory effects; v) risk assessment of adjuvant and immunogenic behaviour of proteins requires specific methodologies that can be adapted from other fields; vi) adjuvanticity and immunogenicity of Cry proteins in certain experimental conditions seems plausible but due to low dosage, oral route of administration, food and feed processing and digestion, it is unlikely to emerge as a safety issue in food and feed; vii) eliciting an immune response is a very complex matter as the body responds to immune offence by inducing many processes. Based on these considerations, it is expected that the availability of new humanized animal models and the possibility to deploy artificial intelligent systems on the vastity of human data will become a general direction aiming to help answering specific questions relating to the immune systems, including the adjuvanticity and immunogenicity of food/feed proteins.

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Cry1Ac protoxin from Bacillus thuringiensis promotes macrophage activation by upregulating CD80 and CD86 and by inducing IL-6, MCP-1 and TNF-α cytokines

Cited by 41 publications

References 46 publications

An overview of the safety and biological effects of Bacillus thuringiensis Cry toxins in mammals

An overview of the safety and biological effects of Bacillus thuringiensis Cry toxins in mammals

No Adjuvant Effect of Bacillus thuringiensis-Maize on Allergic Responses in Mice

Literature review in support of adjuvanticity/immunogenicity assessment of proteins

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