Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-06-16T07:46:41Z 2016-01-22T07:08:46Z

Pro-inflammatory cytokines (mouse) for more info:<div>http://www.ncbi.nlm.nih.gov/mesh/68016207</div>

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<font face="Arial, Verdana" size="2">O-antigen (mouse) for more info:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68019081</font></div>

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respiratory bacterium Bordetella bronchiseptica 

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<span lang="EN-GB">Th2\r\ncells in systemic compartment (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68018418</span></div>

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<font face="Arial, Verdana" size="2">Dendritic cells in lungs/small intestine, for more info:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68003713</font></div>

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<span lang="EN-GB">T\r\nregulatory cells in systemic compartment (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68050378</span></div>

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Antibody A (mouse)

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<span lang="EN-GB">Type\r\nthree secretion system in systemic compartment (mouse)</span>

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Antigen-antibody complexes

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Interleukin 4 in the small intestines/lungs (mouse)<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P07750" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P07750</a></div>

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Antibody G (mouse)

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<span lang="EN-GB">Interleukin\r\n4 in systemic compartment (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P07750" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P07750</a></div>

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<span lang="EN-GB">T\r\nhelper cells subtype I in lungs/small intestine (mouse) </span>

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<font face="Arial, Verdana" size="2">Macrophages in the lungs (mouse) for more info:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68008264</font><br/><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><br/></div></div>

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<span lang="EN-GB">Interleukin\r\n10 in systemic compartment (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P18893" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P18893</a></div>

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Interleukin 12 in lungs/intestine (mouse)

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<span lang="EN-GB">Interleukin\r\n10 in lungs/small intestine (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P18893" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P18893</a></div>

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<span lang="EN-GB" style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Recruited\r\nneutrophils (mouse) for more info:</span><div><span lang="EN-GB"><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68009504</font></span></div>

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<span lang="EN-GB">T\r\nhelper cells subtype I in systemic compartment (mouse)</span>

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Interferon gamma in lungs/small intestine (mouse)

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<font face="Arial, Verdana" size="2">Epithelial cells in lung/intestine (mouse) for more info:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68004847</font></div>

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<font face="Arial, Verdana" size="2">Complement cascade for more info:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/?term=complement+cascade</font></div>

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Referred to as DNE (dead neutrophils) in Thakar et. al paper

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Dendritic cells in the systemic compartment, more info:<div>http://www.ncbi.nlm.nih.gov/mesh/68003713</div>

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<font face="Arial, Verdana" size="2">B-Lymphocytes. See link:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68001402</font></div>

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Naive T cells (mouse)

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Activated phagocytes

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Type three secretion system in the lungs (mouse)

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<span lang="EN-GB">T\r\nregulatory cells in lungs/small intestine (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68050378</span></div>

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<span style="font-family: arial, sans-serif; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: 18.0049991607666px; color: rgb(51, 51, 51); background-color: rgb(255, 255, 255);">Interferon gamma in systemic compartment (mouse) more info:</span><div><span style="background-color: rgb(255, 255, 255); line-height: 18.0049991607666px;"><font color="#333333" face="arial, sans-serif" size="2">http://www.ncbi.nlm.nih.gov/mesh/68007371</font></span></div>

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Represents pH<div><br/></div><div>Phagocytosis (mouse) in coninfection for more info:</div><div>http://www.ncbi.nlm.nih.gov/mesh/68010587</div><div><hr/></div><div><br/></div><div>PH protein in the Drosophila segmentation model (2013)</div>

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<span lang="EN-GB">Interleukin\r\n12 in systemic compartment (mouse)</span>

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<div>EC positively regulates PIC [1]. DP positively regulates PIC [1]. AP activates PIC [1]. IL10I negatively regulates PIC [1].</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">AP activates PIC [1]</span>

"Upon detection, epithelial cells activate pro-inflammatory cytokines" [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">DP activates PIC [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IL10I negatively regulates PIC [1]</span>

S_27 1 S_17 1 S_23 1 S_17 1 S_21 1 S_17 1

Bb positively regulates Oag [1].

S_3 1

Bb self regulates. PH negatively regulates Bb [1].

PH negatively regulates Bb [1].

Bb positively regulates itself [1].

S_3 1 S_32 1

<div>DCII in conjunction with T0 activates Th2II [1]. IL12II inhibites Th2II [1].</div><div><p class="MsoNormal" style="margin-bottom: 0.0001pt;"><br/></p></div>

DCII in conjunction with T0 activates Th2II [1]. 

IL12II inhibites Th2II [1].

DCII in conjunction with T0 activates Th2II [1]. 

S_24 1 S_26 1 S_33 1

<div>Bb in conjunction with IFNgI activates DCI [1]. Bb in conjunction with PIC positively regulates DCI [1].</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Bb in conjunction with IFNgI activates DCI [1]. Bb in conjunction with PIC positively regulates DCI [1].</span>

S_1 1 S_3 1 S_20 1 S_3 1

DCII in conjunction with T0 positively regulate TrII [1].

DCII in conjunction with T0 positively regulate TrII [1]

S_24 1 S_26 1

<div>Bb in conjunction with BC positively regulates IgA [1,2,3,4]. Bb in conjunction with IgA positively regulates IgA [1].</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><br/></div>

Bb in conjunction with BC positively regulates IgA [1,2,3,4]. <div>Bb in conjunction with IgA positively regulates IgA [1].</div>

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">Activation of B cells by T helper cells led to the prompt increase of peripheral antibodies (serum IgG and IgA)</span>" [1,2,3,4]

S_7 1 S_3 1 S_25 1 S_3 1

TTSSI positively regulates TTSSII [1].

S_28 1

<span lang="EN-GB" style="font-size:12.0pt;line-height:\r\n115%;font-family:"Times New Roman","serif";mso-fareast-font-family:"Times New Roman";\r\nmso-ansi-language:EN-GB;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Bb positively regulates AgAb in conjunction with IgG [1].  </span><span style="font-family: 'Times New Roman', serif; font-size: 16px; line-height: 18.399999618530273px;">Bb positively regulates AgAb in conjunction with IgA [1]. </span>

<span style="font-family: 'Times New Roman', serif; font-size: 16px; line-height: 18.399999618530273px;">Bb positively regulates AgAb in conjunction with IgA [1].</span><span style="font-family: 'Times New Roman', serif; font-size: 16px; line-height: 18.399999618530273px;"> </span><div><span style="font-family: 'Times New Roman', serif; font-size: 16px; line-height: 18.399999618530273px;">Bb positively regulates AgAb in conjunction with IgG [1].</span><span style="font-family: 'Times New Roman', serif; font-size: 16px; line-height: 18.399999618530273px;"> </span></div>

<span style="font-family: 'Times New Roman', serif; font-size: 16px; line-height: 18.399999618530273px;">Bb positively regulates AgAb in conjunction with IgG [1].</span><span style="font-family: 'Times New Roman', serif; font-size: 16px; line-height: 18.399999618530273px;"> </span>

S_11 1 S_3 1 S_7 1 S_3 1

IL4II positively regulates IL4I [1].

IL4II positively regulates IL4I [1]

S_12 1

BC positively regulates IgG [1,2,3,4]. IgG positively regulates itself [1].

<span lang="EN-GB">Activation of B cells by T helper cells led to\r\nthe prompt increase of peripheral antibodies (serum IgG and IgA) [1,2,3,4]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">IgG positively regulates itself [1]</span>

S_11 1 S_25 1

<div>DCII in conjunction with T0 positively regulates IL4II [1]. Th2II positively regulates IL4II [1]. IL12II negatively regulates IL4II [1]. IFNgII negatively regulates IL4II [1].</div><div><br/></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IFNgII negatively regulates IL4II [1]</span>

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);"> "Dendritic cells induce differentiation of naïve T cells (T0) by producing IL4" [1]</span>

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">"IL4 is also produced by differentiated Th2 cells" [1]</span>

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">"IL4 and IL12 inhibit each other" [1]</span>

S_4 1 S_30 1 S_33 1 S_24 1 S_26 1 S_30 1 S_33 1

Th1II positively regulates Th1I [1].

Th1II positively regulates Th1I [1]

S_19 1

<div>Bb in combination with PIC activates MPI [1]. Bb in combination with IFNgI activates MPI [1]. </div>

Bb in combination with PIC activates MPI [1].<div>Bb in combination with IFNgI activates MPI [1]. </div>

"macrophages were recruited by IFN? secreted by Th1 cells" [1]<div><br/></div><div>Bb in combination with IFNgI activates MPI [1].</div>

Bb in combination with PIC activates MPI [1]. 

S_20 1 S_3 1 S_1 1 S_3 1

IL10I positively regulates Il10II [1].

IL10I positively regulates Il10II [1]

S_17 1

<div>DCII in conjunction with T0 positively regulates IL12I [1]. IL4II negatively regulates IL12I [1].</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">DCII in conjunction with T0 positively regulates IL12I [1]</span>

IL4II inhibits IL12I [1]

S_24 1 S_26 1 S_12 1

<div>Th2I in conjunction with TTSSI positively regulates IL10I [1]. TrI positively regulates IL10I [1]. MPI positively regulates IL10I [1].</div>

<font color="#333333" face="arial, sans-serif"><span style="line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">"</span></font><span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">T regulatory (Treg) cells are stimulated by the type III secretion system of </span><em style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">B. bronchiseptica</em><span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);"> to produce IL10" [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Th2I in conjunction with TTSSI positively regulates IL10I [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">MPI positively regulates IL10I [1]</span>

S_29 1 S_14 1 S_31 1 S_28 1

PIC positively regulates NE [1].

"<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">The rapid recruitment of peripheral neutrophils to the lungs was possible through pro-inflammatory cytokine mediated signalling" [1]</span>

S_1 1

<div>DCII in conjuction with T0 and Il12II positively regulates Th1II [1]. </div>

DCII in conjuction with T0 and Il12II positively regulates Th1II [1]

S_24 1 S_33 1 S_26 1

<p class="MsoNormal" style="margin-bottom: 0.0001pt;"><span lang="EN-GB">Th1I positively regulates IFNgI, while IL10I negatively regulates IFNgI and is dominant over Th1I activity [1]. MPI positively regulates IFNgI [1]. DCI positively regulates IFNgI [1]. IL4I negatively regulates IFNgI [1].</span></p>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">IL4I negatively regulates IFNgI [1].</span>

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">"hosts successfully counteract the pathogen mediated inhibitions by activating a protective Th1 cell mediated IFN? response" [1,2,3,4]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> DCI positively regulates IFNgI [1]</span>

<em style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">B. bronchiseptica</em><span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);"> has been suggested to induce IL10 production by T cell subtypes, which inhibits IFN? in the lower respiratory tract [1,2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">MPI positively regulates IFNgI [1]</span>

S_5 1 S_10 1 S_14 1 S_10 1 S_13 1 S_10 1 S_17 1

Bb positively regulates EC [1].

B. brontiseptica activates EC [1].

S_3 1

<div>AgAb in conjunction with IgG positively regulates C [1]. Oag negatively regulates C [1]. Bb positively regulates C [1].</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">AgAb in conjunction with IgG positively regulates C [1].</span>

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">Activation of complement by bacteria is inhibited by O-antigen [1]</span>

Oag negatively regulates C, with dominance over positive regulator Bb [1].

S_3 1 S_2 1 S_11 1 S_9 1

<div>NE in conjuction with TTSSI positively regulate DP (DNE) [1].</div>

NE in conjuction with TTSSI positively regulate DP (DNE) [1].

S_18 1 S_28 1

DCI positively regulates DCII [1].

S_5 1

T0 positively regulates BC. BC positively regulates itself [1].

BC positively regulates itself [1].

T0 positively regulates BC [1].

S_25 1 S_26 1

DCII positively regulates T0 [1].

"Dendritic cells induce differentiation of naïve T cells (T0) by producing IL4 and IL12" [1]

S_24 1

<div>Bb, MPI, and Th1I in combination with C and IgG activate AP [1]. <span style="font-size: 10pt;">Bb, MPI, and Th11 in combination with AgAb activate AP [1].</span></div><div><br/></div>

Bb, MPI, and Th1I in combination with C and IgG activate AP [1].

Bb, MPI, and Th11 in combination with AgAb activate AP [1].

Bb, MPI, and Th1I in combination with C and IgG or AgAb activate AP [1].

Bb, MPI, and Th1I in combination with C and IgG activate AP [1].

Bb, MPI, and Th1I in combination with C and IgG or AgAb activate AP [1].

S_11 1 S_13 1 S_14 1 S_3 1 S_22 1 S_9 1 S_3 1 S_13 1 S_14 1

<div>Bb activates TTSSI [1]. IgG inhibits TTSSI [1]. <span style="font-size: 10pt;">IgA inhibits TTSSI [1].</span></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IgA inhibits TTSSI [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">Bb activates TTSSI [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IgG inhibits TTSSI [1].</span>

S_3 1 S_7 1 S_11 1

TrII positively regulates TrI [1]. 

TrII positively regulates TrI [1]

S_6 1

IFNgI positively regulates IFNgII [1].

S_20 1

Th2II positively regulates Th2I [1].

S_4 1

AP in conjunction with Bb activate PH [1].

"The node “activated phagocytic cells” represents the outcome of the stimulation of neutrophils and macrophages by antibody-antigen complex and complement. These cells induce the node phagocytosis that depletes bacteria" [1]

AP in conjunction with Bb activate PH [1].

S_27 1 S_3 1

<div>DCII in conjunction with T0 positively regulates IL12II [1]. IL4II negatively regulates IL12II [1].</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IL4II negatively regulates IL12II [1].</span>

S_24 1 S_26 1 S_12 1